Indane or dihydroindole derivatives

ABSTRACT

The present invention relates to substituted indane or dihydroindole compounds of Formula (I)  
                 
 
     wherein A is an indole. These compounds have high affinity for D 4  receptors.

FIELD OF THE INVENTION

[0001] The present invention relates to a novel class of substitutedindane or dihydroindole compounds having effect at dopamine D₄receptors. The compounds are selective dopamine D₄ ligands or they havecombined effects at dopamine D₄, 5-HT receptors and/or the 5-HTtransporter. These compounds are therefore useful in the treatment ofcertain psychiatric and neurologic disorders, including psychosis,depression and anxiety.

BACKGROUND OF THE INVENTION

[0002] Compounds related to the compounds of the present invention areknown from DE patent application No. 4414113 describing certain4-(indol-3-yl)-1-(indol-3-yl-alkylene)-piperidines. The compounds hereinare claimed to show serotonin antagonistic and agonistic activities andto have effect on DOPA-accumulation in straitum. No biological data aregiven.

[0003] GB patent application No. 2 044 254 describes certain1-(indol-3-yl-alkylene)-piperidine derivatives which are substituted inposition 3 or 4 of the piperidine ring with an isoindole, or anisoquinoline ring. These compounds are claimed to have 5-HT reuptakeinhibiting activity and to be useful as antidepressants.

[0004] Furthermore, in WO patent publications No. WO 9421627, WO 9421630and WO 9421626 various series of indolyl- or indazolylmethyl piperidineor piperazine derivatives are described to be selective dopamine D₄antagonists. No data are given. The compounds are only said to giveK_(i) values of less than 1.5 μM in a test for displacement of ³Hspiperone from human dopamine D₄ receptor subtypes in clonal cell lines.

[0005] WO patent publication No. 95/33721 relates to 1-(indanemethyl,dihydrobenzofuranylmethyl, or dihvdrobenzothiophenylmethyl)piperidine,-tetrahydropyridine, or piperazine derivatives. The 1-indanemethylcompounds disclosed herein are substituted in position 6 with an aminocontaining group. The compounds interact with central 5-HT receptors, inparticular with 5-HT_(1A) and 5-HT_(2A) receptors. Some of the compoundsare said to have 5-HT reuptake inhibiting effect.

[0006] Dopamine D₄ receptors belong to the dopamine D₂ receptor familywhich is considered to be responsible for the antipsychotic effects ofneuroleptics. Dopamine D₄ receptors are primarily located in areas ofthe brain other than striatum (Van Tol, et al. Nature, 1991, 350, 610).The low level of D₄ receptors in striatum suggesting that compoundswhich are selective for the dopamine D₄ receptor will be devoid ofextrapyramidal activity, is illustrated by the antipsychotic clozapinewhich has a high affinity for dopamine D₄ receptors and is lackingextrapyramidal side effects, (Van Tol, et al. Nature, 1991, 350, 610).Also, dopamine D₄ receptor levels have been reported to be elevated inschizophrenic patients (Seeman et al., Nature, 1993, 365, 441.).

[0007] Various effects are known with respect to compounds which areligands at the different serotonin receptor subtypes. As regards the5-HT_(2A) receptor, which was previously referred to as the 5-HT₂receptor, the following effects have e.g. been reported:

[0008] Antidepressive effect and improvement of the sleep quality(Meert, T. F.; Janssen, P. A. J. Drug. Dev. Res. 1989, 18, 119.)reduction of the negative symptoms of schizophrenia and ofextrapyramidal side-effects caused by treatment with classicalneuroleptics in schizophrenic patients (Gelders, Y. G., British J.Psychiatry, 1989, 155 (suppl. 5, 33). Finally, selective 5-HT_(2A)antagonists could be effective in the prophylaxis and treatment ofmigraine (Scrip Report; “Migraine— Current trends in research andtreatment”; PJB Publications Ltd.; May 1991).

[0009] Clinical studies have shown that 5-HT_(1A) partial agonists areuseful in the treatment of anxiety disorders such as generalised anxietydisorder, panic disorder, and obsessive compulsive disorder (Glitz, D.A., Pohl, R., Drugs 1991, 41, 11). Preclinical studies indicate thatfull agonists are useful in the treatment of the above mentioned anxietyrelated disorders (Schipper, Human Psychopharmacol., 1991, 6, S53).

[0010] There is evidence, both clinical and preclinical, in support ofthe beneficial effect of 5-HT_(1A) partial agonists in the treatment ofdepression, impulse control disorders and alcohol abuse (van Hest,Psychopharmacol., 1992, 107, 474; Schipper et al, HumanPsychopharmacol., 1991, 6, S53; Cervo et al, Eur. J. Pharm., 1988, 158,53; Glitz and Poh, Drugs 1991, 41, 11; Grof et al., Int. Clin.Psychopharmacol. 1993, 8, 167-172; Ansseau et al., HumanPsychopharmacol. 1993, 8, 279-283).

[0011] 5-HT_(1A) agonists and partial agonists inhibit isolation-inducedaggression in male mice indicating that these compounds may be useful inthe treatment of aggression (Sanchéz et al., Psychopharmacology, 1993,110, 53-59).

[0012] Furthermore, 5-HT_(1A) ligands have been reported to showantipsychotic effect in animal models (Wadenberg and Ahlenius, J.Neural. Transm., 1991, 83, 43; Ahlenius, Pharmacol. & Toxicol., 1989,64, 3; Lowe et al., J. Med. Chem., 1991, 34, 1860; New et al., J. Med.Chem., 1989, 32, 1147; and Martin et al., J. Med. Chem., 1989, 32,1052).

[0013] Recent studies also indicate that 5-HT_(1A) receptors areimportant in the serotonergic modulation of haloperidol-inducedcatalepsy (Hicks, Life Science 1990, 47, 1609, Wadenberg et al.Pharmacol. Biochem. & Behav. 1994, 47, 509-513) suggesting that5-HT_(1A) agonists are useful in the treatment of extrapyramidalside-effects induced by conventional antipsychotic agents such ashalopendol.

[0014] 5-HT_(1A) agonists have shown neuroprotective properties inrodent models of focal and global cerebral ischaemia and may, therefore,be useful in the treatment of ischaemic disease states (Prehn, Eur. J.Pharm. 1991, 203, 213).

[0015] Pharmacological studies have been presented which indicate that5-HT_(1A) antagonists are useful in the treatment of senile dementia(Bowen et al, Trends Neur. Sci. 1992, 15, 84).

[0016] 5-HT reuptake inhibitors are well known antidepressant drugs.

[0017] Accordingly, dopamine D₄ receptor ligands are potential drugs forthe treatment of psychoses and positive symptoms of schizophrenia andcompounds with combined effects at dopamine D₄ and 5-HT receptors and/orthe 5-HT transporter may have the further benefit of improved effect onother psychiatric symptoms in schizophrenic patients such as depressiveand anxiety symptoms. 5-HT_(1A) and 5-HT_(2A) receptor ligands and 5-HTreuptake inhibitors have different activities in different animal modelspredictive of anxiolytic and antiaggressive effects (Perregaard et al.,Recent Developments in Anxiolytics. Current Opinion in TherapeuticPatents 1993, 1, 101-128) and/or in models predictive of effects inother psychic disorders and it is considered highly beneficial to havesuch combined serotonergic effects.

[0018] Compounds with dopamine D₄ receptor activity combined with effectat 5-HT receptors and compounds with dopamine D₄ receptor activitycombined with 5-HT reuptake inhibiting effect is considered a newtherapeutic approach in the treatment of neurologic and psychiatricdisorders, including in particular psychosis.

SUMMARY OF THE INVENTION

[0019] The object of the present invention is to provide compounds withdopamine D₄ activities or with combined effects at dopamine D₄receptors, 5-HT receptors and/or the 5-HT transporter

[0020] It has now been found that certain substituted indane ordihydroindole compounds have effect at dopamine D₄ receptors.Additionally, many of the compounds interact with central serotonergicreceptors, in particular with the 5-HT_(1A) and/or the 5-HT_(2A)receptors and/or they act as 5-HT uptake inhibitors.

[0021] Accordingly, the present invention relates to novel compounds ofthe formula I

[0022] wherein A is a group

[0023] Y is a hydrocarbon group completing an indane ring, a group NR¹completing a dihydroindole ring, or a group N completing a dihydroindolering linked via the 1-position;

[0024] W is a bond, and n+m is 1, 2, 3, 4, 5, or 6;

[0025] W is CO, SO, or SO₂, n is 2, 3, 4, or 5 and m is 0, 1, 2, or 3,provided that n+m is not more than 6; or

[0026] W is O, S , n is 2, 3, 4, or 5 and in is 0, 1, 2, or 3, providedthat n+m is not more than 6, and if Y is N completing a dihydroindolering attached via the 1-position then m is 2, or 3; and if Y is NR¹completing a dihydroindole ring linked via the 2-position then m is 1,2, or 3; the dotted line, emanating from X, indicates an optional bond;when it does not indicate a bond, X is N, CH or COH; and when itindicates a bond, X is C;

[0027] R¹ is

[0028] hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, aryl heteroaryl, aryl-C₁₋₆ alkyl,heteroaryl-C₁₋₆-alkyl, acyl, thioacyl, C₁₋₆ alkylsulfonyl,trifluoromethylsulfonyl, arylsulfonyl, or heteroarylsulfonyl

[0029] R¹⁵VCO— wherein V is O or S and R¹⁵ is C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yl, C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, aryl, orheteroaryl; or

[0030] a group R¹⁶R¹⁷NCO— or R¹⁶R¹⁷NCS— wherein R¹⁶ and R¹⁷ areindependently hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, heteroaryl, or aryl, or R¹⁶ andR¹⁷ together with the N-atom to which they are linked, form apyrrolidinyl, piperidinyl or perhydroazepin group;

[0031] R²-R⁵ are independently selected from hydrogen, halogen, cyano,nitro, C₁₋₆-alk(en/yn)yl, C₁₋₆ alkoxy, C₁₋₆-alkylthio, hydroxy,C₃₋₈-cycloalk(en)yl, C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,C₁₋₆-alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl,trifluoromethyl. trifluoromethylsulfonyloxy and C₁₋₆ alkylsulfonyl, oneof R²-R⁵ alternatively being a group —NR¹³R¹⁴ wherein R¹³ is as definedfor R¹ and R¹⁴ is hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆ alk(en/yn)yl, aryl, heteroaryl, aryl-C₁₋₆alkyl, or heteroaryl-C₁₋₆-alkyl, or

[0032] R¹³ and R¹⁴ together with the N-atom to which they are linkedform a group

[0033] wherein Q is C═O, C═S or CH₂; T is NH, N-alkyl, S, O or CH₂; andp is 1-4, inclusive; or two adjacent groups taken from R²-R⁵ may bejoined and designate —(CH₂)₃—, or —CH═CH—NH—, thereby forming a fused 5membered ring;

[0034] R⁶-R⁹ and R¹¹-R¹² are independently hydrogen, halogen, cyano,nitro C₁₋₆-alk(en/yn)yl. C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,C₃₋₈-cycloalk(en)yl, C₃₋₈-cycloalk(en)yl-C₁₋₆ alk(en/yn)yl, aryl,heteroaryl, phenylcarbonyl, halogen substituted phenylcarbonyl,trifluoromethyl.

[0035] or

[0036] C₁₋₆ alkylsulfonyl, or two adjacent groups taken from R⁶-R⁹ maytogether form a methylenedioxy group;

[0037] R¹⁰ is as defined for R¹ above;

[0038] with the proviso that the substituent R³ or R⁴ in position 6 maynot be —NR¹³R¹⁴ when Y is CH₂, W is a bond, n+m is 1 and the ring islinked via the 1-position; or a pharmaceutically acceptable acidaddition salt thereof.

[0039] The compounds of the invention have been found to show highaffinity for dopamine D₄ receptors and some of the compounds have beenfound also to show affinity for serotonergic receptors including5-HT_(1A) receptors and/or for 5-HT_(2A) receptors. An important groupof compounds according to the invention are the compounds which haveeffect at dopamine D₄ receptors combined with 5-HT reuptake inhibitingeffect.

[0040] Accordingly, the compounds of the invention are considered usefulin the treatment of positive and negative symptoms of schizophrenia,other psychoses, anxiety disorders, such as generalised anxietydisorder, panic disorder, and obsessive compulsive disorder, depression,alcohol abuse, impulse control disorders, aggression, side effectsinduced by conventional antipsychotic agents, ischaemic disease states,migraine, senile dementia and cardiovascular disorders and in theimprovement of sleep.

[0041] In another aspect of the present invention provides apharmaceutical composition comprising at least one compound of Formula Ias defined above or a pharmaceutically acceptable acid addition saltthereof in a therapeutically effective amount and in combination withone or more pharmaceutically acceptable carriers or diluents.

[0042] In a further aspect the present invention provides the use of acompound of Formula I as defined above or an acid addition salt thereoffor the manufacture of a pharmaceutical preparation for the treatment ofthe above mentioned disorders.

DETAILED DESCRIPTION OF THE INVENTION

[0043] Some of the compounds of general Formula I exist as opticalisomers thereof and such optical isomers are also embraced by theinvention.

[0044] The expression C₁₋₆-alk(en/yn)yl means C₁₋₆-alkyl, C₂₋₆-alkenyl,or C₂₋₆-alkynyl group.

[0045] The expression C₃₋₈-cycloalk(en)yl means a C₃₋₈-cycloalkyl group,or a C₃₋₈-cycloalkenyl group.

[0046] The term C₁₋₆ alkyl refers to a branched or unbranched alkylgroup having from one to six carbon atoms inclusive, such as methyl,ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and2-methyl-l-propyl.

[0047] Similarly, C₂₋₆ alkenyl and C₂₋₆ alkynyl, respectively, designatesuch groups having from two to six carbon atoms, including one doublebond and triple bond respectively, such as ethenyl, propenyl, butenyl,ethynyl, propynyl, and butynyl.

[0048] The terms C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆alkylamino, C₁₋₆ alkylcarbonyl, etc. designate such groups in which thealkyl group is C₁₋₆ alkyl as defined above.

[0049] The term C₃₋₈ cycloalkyl designates a monocyclic or bicycliccarbocycle having three to eight C-atoms, such as cyclopropyl,cyclopentyl, cyclohexyl, etc.

[0050] The term C₃₋₈ cycloalkenyl designates a monocyclic or bicycliccarbocycle having three to eight C-atoms and containing one double bond.

[0051] The term aryl refers to a carbocyclic aromatic group, such asphenyl, naphthyl, in particular phenyl, including methyl substitutednaphthyl, or phenyl.

[0052] The term heteroaryl refers to a mono- or bicyclic heterocyclicgroup such as indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyland furanyl, in particular pyrimidyl, indolyl, and thienyl.

[0053] Halogen means fluoro, chloro, bromo or iodo.

[0054] As used herein the term acyl refers to a formyl, C₁₋₆alk(en/yn)ylcarbonyl, arylcarbonyl, aryl-C₁₋₆ alk(en/yn)ylcarbonyl,C₃₋₈-cycloalk(en)ylcarbonyl, or a C₃₋₈-cycloalk(en)yl-C₁₋₆alk(en/yn)ylcarbonyl group and the term thioacyl is the correspondingacyl group in which the carbonyl group is replaced with a thiocarbonylgroup.

[0055] One group of compounds according to the invention are thecompounds wherein Y is completing an indane ring.

[0056] Other groups of compounds according to the invention are thegroups of compounds wherein Y is NR¹ or N completing a dihydroindolering.

[0057] Accordingly, one group of compounds are the compounds wherein Yis CH₂ and A is a group a) linked to X via the 2 or the 3 position, or agroup b), in particular a group a).

[0058] Another group of compounds are the compounds wherein Y is CH₂ andA is a group group c) linked to X via the 4, 5, 6, or 7 position.

[0059] A third and fourth group of compounds are the compounds wherein Yis NR¹ or N and A is a group a) linked to X via the 2 or the 3 position,or a group b), in particular a group a).

[0060] A fifth and sixth group of compounds are the compounds wherein Yis NR¹ or N and A is a group c) linked to X via the 4, 5, 6, or 7position.

[0061] Particular embodiments of the present invention are compoundswherein Y is a hydrocarbon group completing an indane ring and

[0062] linked via the 2 position and A is a group a) which is linked viaposition 3;

[0063] linked via the 2 position and A is a group a) which is linked viaposition 2;

[0064] linked via the 2 position and A is a group b);

[0065] linked via the 2 position A is a group c) which is linked viaposition 4, 5, 6, or 7;

[0066] linked via the 1 position A is a group a) which is linked viaposition 3;

[0067] linked via the 1 position and A is a group a) which is linked viaposition 2;

[0068] linked via the 1 position A is a group b), or

[0069] linked via the 1 position and A is a group c) which is linked viaposition 4, 5, 6, or 7.

[0070] Other particular embodiments of the present invention arecompounds wherein Y is NR¹ completing dihydroindole ring which is

[0071] linked via the 3 position and A is a group a) which is linked viaposition 3:

[0072] linked via the 3 position and A is a croup a) which is linked viaposition 2;

[0073] linked via the 3 position and A is a group b);

[0074] linked via the 3 position and A is a group c) which is linked viaposition 4, 3, 6, or 7,

[0075] linked via the 2 position and A is a group a) which is linked viaposition 3,

[0076] linked via the 2 position and A is a group a) which is linked viaposition 2,

[0077] linked via the 2 position and A is a group b); or

[0078] linked via the 2 position and A is a group c) which is linked viaposition 4, 5, 6, or 7.

[0079] Still other particular embodiments of the present invention arecompounds wherein Y is N completing dihydroindole and

[0080] A is a group a) which is linked via position 3;

[0081] A is a group a) which is linked via position 2;

[0082] A is a group b); or

[0083] A is a group c) which is linked via position 4, 5, 6, or 7.

[0084] In one group of compounds W is a bond, n+m is 1 to 4, or n+m isselected from 1 and/or 2. Other groups of compounds are compoundswherein W is a bond n+m is 2 to 6, 2 to 5, 2 to 4, 3 to 6, 3 to 5, or 3to 4.

[0085] When W is not a bond it is O, or CO.

[0086] Three further group of compounds are the compounds wherein X isCH, X is C, and X is N respectively.

[0087] R¹ is in a particular embodiment selected from hydrogen,C₁₋₆-alkyl, formyl, C₁₋₆-alkylcarbonyl, C₁₋₆-alkoxycarbonyl orC₁₋₆-alkylaminocarbonyl.

[0088] In on embodiment of the invention R² to R⁵ are independentlyselected from hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₁₋₆ alkoxy,C₁₋₆-alkylthio, hydroxy, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C ₁₋₆-alkyl,C₁₋₆-alkylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy and C₁₋₆alkylsulfonyl, one of R² to R⁵ alternatively being a group —NR¹³R¹⁴wherein R¹³ is hydrogen, C₁₋₆-alkyl, acyl, C₁₋₂-alkylsulfonyl, or agroup —R¹⁶R¹⁷NCO wherein R¹⁶ is hydrogen, C₁₋₆-alkyl, C₃₋₈-cycloalkyl,or C₃₋₈-cycloalkyl-C₁₋₆-alkyl, and R¹⁷ is hydrogen or C₁₋₆-alkyl, or R¹⁶and R¹⁷ together with the N-atom to which they are linked, form apyrrolidinyl, piperidinyl, or perhydroazepin group and R¹⁴ is hydrogenor C₁₋₆-alkyl, or R¹³ and R¹⁴ are linked together to form pyrrolidinyl,piperidinyl, perhydroazepin or a 5 to 7 membered unsubstituted lactamring, in particular R² to R⁵ is selected from hydrogen, halogen, cyano,nitro, C₁₋₆-alkyl, C₁₋₆-alkoxy, trifluoromethyl, andtrifluoromethylsulfonyloxy.

[0089] In one group of compounds according to the invention n one ofR²-R⁵ is a group NR, ¹³R¹⁴, and in another group of compounds accordingto the invention at least one of R²-R⁵ is a group NR¹³R¹⁴, wherein R¹³is preferably selected from methyl, formyl, acetyl, methylaminocarbonyl,dimethylaminocarbonyl, methylsulfonyl, aminocarbonyl,cyclopropylcarbonyl, pyrrolidinylcarbonyl

[0090] or

[0091] 4-fluorophenylaminocarbonyl and R¹⁴ is preferably selected fromhydrogen or C₁₋₆-alkyl.

[0092] Another particular group of compounds according to the inventionare compounds wherein two adjacent groups taken from R² to R⁵ are joinedand designate —CH═CH—NH—, thereby forming a fused 5 membered ring.

[0093] In one embodiment of the invention R⁶ to R⁹ are independentlyselected from hydrogen, halogen. cyano, nitro, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, hydroxy, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C ₁₋₆ alkyl,trifluoromethyl, and C₁₋₆ alkylsulfonyl, or two adjacent groups takenfrom R⁶-R⁹ may be joined and designate a methylenedioxy group, inparticular R⁶ to R⁹ are independently selected from hydrogen, halogen,C₁₋₆-alkyl, C₁₋₆-alkoxy, or two adjacent groups taken from R⁶-R ⁹ may bejoined and designate a methylenedioxy group.

[0094] A subgroup of compounds are the compounds wherein at least one ofR⁸ and R⁹ is hydrogen and R⁶ to R⁷ are independently hydrogen orhalogen, in particular chloro.

[0095] Specific examples of R¹¹ and R¹² are hydrogen or C₁₋₆-alkyl, andR¹⁰ is hydrogen, C₁₋₆-alkyl, or acyl.

[0096] Preferred compounds are compounds selected from

[0097]6-Chloro-3-[1-(6-bromo-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0098] 3-[1-(1-Indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0099] 3-[1-(1-Indanylmethyl)piperindin-4-yl]-1H-indole,

[0100]6-Chloro-3-[1-(7-methoxyindan-1-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole.

[0101]3-[1-(6-Methoxyindan-1-yl)methyl-1,2,3,6-tetrahydropyridin4-yl]-1H-indole,oxalate,

[0102]6-Chloro-3-[1-(6-cyano-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0103] 6-Chloro-3-[1-(6-cyano-1-indanylmethyl)piperidin-4-yl]-1H-indole,

[0104]6-Chloro-3-[1-(4-acetylamino-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0105]6-Chloro-3-[1-(5-acetylamino-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0106]6-Chloro-3-[1-(6-bromo-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0107]6-Chloro-3-[1-[2-(indane-1-yl)ethyl]-1,2,3,6-tetrahydropyridine-4-yl]-1H-indole,

[0108]5-Fluoro-3-[1-[2-(indan-1-yl)ethyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0109] 5-Fluoro-3-[1-[2-(indan-1-yl)ethyl]-piperidin-4-yl]-1H-indole,

[0110]5-Fluoro-3-[1-[4-(indan-1-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0111]5-Fluoro-3-[1-[4-(indan-1-yl)butan-1-yl]-piperidin-4-yl]-1H-indole,

[0112]6-Chloro-3-[1-[4-(indan-1-yl)butan-1-yl]-piperidin-4-yl]-1H-indole,

[0113]6-Chloro-3-[1-[3-(indan-1-yl)propan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0114]6-Chloro-3-[1-[4-(indane-1-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0115]6-Chloro-3-[1-(indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0116] 3-[(Indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0117]7-Chloro-3-[1-indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0118]6,7-Dichloro-3-[1-(indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0119]3-[1-(Indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-5,6-methylenedioxy-1H-indole,

[0120] 5-[4-(Indan-2-yl)methylpiperazin-1-yl3-1H-indole,

[0121]6-Chloro-3-[1-[2-(indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0122]6-Chloro-3-[1-[3-(indan-2-yl)propan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0123]6-Chloro-3-[1-[4-(indan-2-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0124]3-[1-[(4-(2-Propyl)oxyindan-2-yl)methyl]piperidin-4-yl]-6-chloro-1H-indole,

[0125]4-[4-(6-Chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-ylmethyl]-1,4,5,6-tetrahydrocyclopent[e]indole,

[0126]6-Chloro-3-[1-(4-acetylaminoindan-2-yl)methyl-1,2,3,6-tetrahydropyridine-4-yl]-1H-indole,

[0127]6-Chloro-3-[1-(4-acetylaminoindan-2-yl)methylpiperidin-4-yl]-1H-indole,

[0128]6-Chloro-3-[1-[2-(6-acetylaminoindan-1-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0129]6-Chloro-3-[1-[3-(6-acetylaminoindan-1-yl)propan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0130]6-Chloro-3-[1-[4-(6-acetylaminoindan-1-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0131]3-[1-(5-Acetylaminoindan-2-yl)methyl-1,2,3,6-tetrahydropyridine-4-yl]-6-chloro-1H-indole,

[0132]3-[1-(5-Acetylaminoindan-2-yl)methylpiperid-4-yl]-6-chloro-1H-indole,

[0133]3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0134]3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperidin-4-yl-6-chloro-1H-indole,

[0135]6-Chloro-3-[1-[2-(1-formyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0136] 6-Chloro-3-[1-[2-(l-formyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperidin4-yl]-1H-indole,

[0137] 3-[1-[2-(1-Acetyl-5-bromo-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0138]3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-7-chloro-1H-indole,

[0139]3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6,7-dichloro-1H-indole,

[0140]3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-5,6-methylenedioxy-1H-indole,

[0141]3-[1-[2-(1-tert-Butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0142]5-[4-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl-1H-indole,

[0143]3-[1-[3-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)propan-1-yl]-1,2,3,6-tetrahydropyridin4-yl]-6-chloro-1H-indole,

[0144]3-[1-[2-(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0145]3-[1-[2-(1-Acetyl-5-methyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0146] 6-Chloro-3-[1-(indan-2-ylmethyl)piperidin-4-yl]-1H-indole,

[0147] 3-[1-(Indan-2-ylmethyl)piperidin-4-yl]-1H-indole,

[0148] 7-Chloro-3-[1-(indan-2-ylmethyl)piperidin-4-yl]-1H-indole,

[0149] 6,7-Dichloro-3-[1-(indan-2-ylmethyl)piperidin-4-yl]-1H-indole,

[0150]3-[1-(Indan-2-ylmethyl)piperidin-4-yl]-5,6-methylenedioxy-1H-indole,

[0151] 6-Chloro-3-[1-[2-(indan-2-yl)ethyl]piperidin-4-yl]-1H-indole,

[0152]6-Chloro-3-[1-[3-(indan-2-yl)propan-3-yl]piperidin-4-yl]-1H-indole,

[0153]6-Chloro-3-[1-[4-(indan-2-yl)butan-4-yl]piperidin-4-yl]-1H-indole,

[0154] 4-[4-[2-(Indan-2-yl)ethyl]piperazin-1-yl]-1H-indole,

[0155] 5-[4-[2-(Indan-2-yl)ethyl]piperazin-1-yl]-1H-indole,

[0156]5-Chloro-1-[1-[2-(indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole,

[0157]1-[1-[2-(Indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0158]2-[1-[2-(Indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0159] 5-Chloro-1-[1-[2-(indan-2-yl)ethyl]piperidin-4-yl]-1H-indole,

[0160] 1-[1-[2-(Indan-2-yl)ethyl]piperidin-4-yl]-1H-indole,

[0161]6-Chloro-3-t1-[2-(2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0162]6-Chloro-3-[1-4-(2,3-dihydro-1H-indol-3-yl)butyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0163]6-Chloro-3-[1-[2-(2,3-dihydro-1-methylaminocarbonyl-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0164](+)-(3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0165](−)-(3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0166]3-[1-[4-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)butyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0167]6-Chloro-3-[1-[6-chloro-1-indanylmethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0168]6-Chloro-3-[1-[6-nitro-1-indanylmethyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0169]6-Chloro-3-[1-[6-fluoro-1-indanylmethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0170]6-Chloro-3-[1-[5-chloro-1-indanylmethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0171]6-Chloro-3-[1-[6-methyl-1-indanylmethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0172]6-Chloro-3-[1-(1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1-methyl-1H-indole,

[0173]6-Chloro-3-[1-[1-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1-(2-propyl-1H-indole,

[0174]5-Fluoro-3-[1-[6-(trifluoromethyl)-1-indanylmethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0175]5-Fluoro-3-[1-[5-(trifluoromethylsulfonyloxy)-1-indanylmethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0176]6-Chloro-3-[1-[1-indanylmethyloxyethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0177]5-Fluoro-3-[1-[6-(indan-1-yl)hexan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0178]3-[1-2-(1-Acetyl-5-fluoro-2,3-dihydro-1-indol-3-yl)ethyl]piperidin-4-yl]-6-chloro-1H-indole,

[0179]6-Chloro-3-[1-[2-(1-formyl-5-fluoro-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0180]6-Chloro-3-[1-[2-(5-fluoro-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0181]6-Chloro-3-[1-[2-(5-fluoro-2,3-dihydro-1-methylaminocarbonyl-1H-indol-3-yl)ethyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0182]6-Chloro-3-[1-[2-(2,3-dihydro-1-mesylaminocarbonyl-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0183]6-Chloro-3-[1-[2-(5-fluoro-2,3-dihydro-1-mesylaminocarbonyl-1H-indol-3-yl)ethyl1-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0184]3-[1-[(1-Acetyl-2,3-dihydro-1H-indol-2-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0185]3-[1-[(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-2-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0186]3-[1-[(1-Acetyl-2,3-dihydro-1H-indol-2-yl)methyl]piperidin-4-yl]-6-chloro-1H-indole,

[0187]3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0188]3-[1-2-(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0189]3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-2-yl)ethyl]piperidin-4-yl]-6-chloro-1H-indoIe,

[0190]6-Chloro-3-[1-[2-(2,3-dihydro-1H-indol-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0191]6-Chloro-3-[1-[2-(5-fluoro-2,3-dihydro-1H-indol-2-yl)ethyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0192] 6-Chloro-2-[4-[(indan-2-yl)methyl]piperazin-1-yl]-1H-indole,

[0193] 6-Chloro-2-[4-[2-(indan-2-yl)ethyl]piperazin-1-yl]-1H-indole,

[0194]2-[4-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-6-chloro-1H-indole,

[0195]2-[4-[2-(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-6-chloro-1H-indole,

[0196] 6-Chloro-3-[4-[(indan-2-yl)methyl]piperazin-1-yl]-1H-indole,

[0197] 6-Chloro-3-[4-[2-(indan-2-yl)ethyl]piperazin-1-yl]-1H-indole,

[0198]3-[4-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-6-chloro-1H-indole,

[0199]3-[4-[2-(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-6-chloro-1H-indole.

[0200] 4-[4-[(Indan-2-yl)methyl]piperazin-1-yl]-1H-indole,

[0201]4-[4-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-1H-indole,

[0202]4-[4-[2-(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-1H-indole,

[0203] 7-[4-[(Indan-2-yl)methyl]piperazin-1-yl]-1H-indole,

[0204] 7-[4-[2-(Indan-2-yl)ethyl]piperazin-1-yl]-1H-indole,

[0205]7-[4-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-1H-indole,

[0206]7-[4-[2-(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-1H-indole,

[0207]2-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0208]2-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-5-chloro-1H-indole,

[0209]2-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperidin-4-yl]-1H-indole,

[0210]2-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperidin-4-yl]-5-chloro-1H-indole,

[0211]2-[1-(Indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0212]5-Chloro-2-[1-(indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0213]5-Chloro-2-[1-(2-(indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0214] 2-[1-(Indan-2-yl)methylpiperidin-4-yl]-1H-indole,

[0215] 5-Chloro-2-[1-(indan-2-yl)methylpiperidin-4-yl]-1H-indole,

[0216] 2-[1-[2-(Indan-2-yl)ethyl]piperidin-4-yl]-1H-indole,

[0217] 5-Chloro-2-[1-[2-(indan-2-yl)ethyl]piperidin-4-yl]-1H-indole,

[0218]7-[4-[(6-Chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]methyl]-3,6,7,8-tetrahydrocyclopent[e]indole,

[0219]7-[4-[(6-Chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]methyl]-1,5,6,7-tetrahydrocyclopent[f]indole,

[0220]6-[4-[(6-Chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyrid-1-yl]methyl]-1,6,7,8-tetrahydrocyclopent[g]indole,

[0221]7-[4-[(6-Chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyrid-1-yl]methyl]-1,6,7,8-tetrahydrocyclopent[g]indole,

[0222](+)6-Chloro-3-[1-[2-(2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0223]6-Chloro-3-[1-[2-(2,3-dihydro-1H-indol-1-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0224]6-Chloro-3-[1-[2-(2,3-dihydro-1H-indol-1-yl)ethyl]-piperidin-4-yl]-1H-indole,

[0225]6-Chloro-3-[1-[3-(2,3-dihydro-1H-indol-1-yl)propan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0226]6-Chloro-3-[1-[4-(2,3-dihydro-1H-indol-1-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,

[0227]6-Chloro-3-[1-[3-(2,3-dihydro-1H-indol-1-yl)-3-oxopropan-1-yl]-1,2,3,6-tetrahydopyrid-4-yl]-1H-indole,

[0228]3-[1-[(5-(2-Propyl)oxyindan-2-yl)methyl]piperidin-4-yl]-6-chloro-1H-indole,

[0229]3-[1-[(5,6-Dimethoxyindan-2-yl)methyl]piperdin-4-yl]-6-chloro-1H-indole,

[0230]3-[1-[(4-(2-Propyl)oxyindan-1-yl)methyl]piperidin-4-yl]-6-chloro-1H-indole,

[0231]3-[1-[(5-(2-Propyl)oxyindan-1-yl)methyl]piperidin-4-yl]-6-chloro-1H-indole,

[0232]3-[1-[(7-Methoxyindan-1-yl)methyl]piperidin-4-yl]-6-chloro-1H-indole,

[0233]3-[1-[(5,6-Dimethoxyindan-1-yl)methyl]piperidin-4-yl]-6-chloro-1H-indole,

[0234]3-[1-[(4-(2-Propyl)oxyindan-2-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0235]3-[1-[(5-(2-Propyl)oxyindan-2-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0236]3-[1-[(5,6-Dimethoxyindan-2-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0237]3-[1-[(4-(2-Propyl)oxyindan-1-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0238]3-[1-[(5-(2-Propyl)oxyindan-1-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,

[0239]3-[1-[(7-Methoxyindan-1-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole.

[0240]3-[1-[(5,6-Dimethoxyindan-1-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,or

[0241]3-[4-[(5,6-Dimethoxyindan-1-yl)methyl]-piperazin-1-yl]-6-chloro-1H-indole,

[0242] and pharmaceutically acceptable acid addition salts thereof.

[0243] The acid addition salts of the compounds of the invention arepharmaceutically acceptable salts formed with non-toxic acids. Exemplaryof such organic salts are those with maleic, fumaric, benzoic, ascorbic,succinic, oxalic, bis-methylenesalicylic, methanesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric,gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic,benzenesulfonic, and theophylline acetic acids, as well as the8-halotheophyllines, for example 8-bromotheophylline Exemplary of suchinorganic salts are those with hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, and nitric acids.

[0244] The pharmaceutical compositions of this invention or those whichare manufactured in accordance with this invention may be administeredby any suitable route, for example orally in the form of tablets,capsules, powders, syrups, etc., or parenterally in the form ofsolutions for injection. For preparing such compositions, methods wellknown in the art may be used, and any pharmaceutically acceptablecarriers, diluents, excipients, or other additives normally used in theart may be used.

[0245] Conveniently, the compounds of the invention are administered inunit dosage form containing said compounds in an amount of about 0.01 to100 mg.

[0246] The total daily dose is usually in the range of about 0.05-500mg, and most preferably about 0.1 to 50 mg of the active compound of theinvention.

[0247] The compounds of the invention may be prepared as follows:

[0248] 1) Alkylating a piperazine, piperidine, or tetrahydropyridine ofthe formula II with an alkylating derivative of the formula III:

[0249] wherein R²-R⁵, X, Y, A, n, m. W, and the dotted line are aspreviously defined, and L is a leaving group such as eg. halogen,mesylate, or tosylate:

[0250]2) Reducing the amide carbonyl in a compound of the followingFormula IV:

[0251] wherein R²-R⁵, X, Y, A, m, W and the dotted line are aspreviously defined and r is n−1 and n is as defined above;

[0252] 3) Introducing a substituent R²′, R³′, R⁴′ or R⁵′ by reacting acompound of the following Formula V:

[0253] wherein one of R²′-R⁵′ is hydrogen and the others are thecorresponding R², R³, R⁴, or R⁵ as previously defined and X, Y , A, m,n, W, and the dotted line are as previously defined, by using a reactivereagent such as a halogen or a halogenating agent, a sulfonating agent,a nitration agent or a reactive agent generating carbonium ions (RCO⁺,R⁺) wherein R is alkyl alkynyl, aryl cycloalkyl, or cycloalk(en/yn)yl;

[0254] 4) Reducing the double bond in an indole compound of thefollowing Formula VI:

[0255] wherein R²-R⁵, R¹, X, n, m, W, and A are as previously defined;

[0256] 5) Reducing the tetrahydropyridinyl double bond in derivatives ofthe following Formula VII

[0257] wherein R²-R⁵, Y, n, m, W, and A are as previously defined;

[0258] 6) Reacting a dihydroindole derivative of formula VIII:

[0259] wherein R²-R⁵, X, A, n, m, W, and the dotted line are aspreviously defined, with a reagent of the formula R¹-L, where L is aleaving group such as halogen, mesylate or tosylate and R¹ is aspreviously defined, or of the formula R¹′—hal or R¹′—OCOR, in whichformulas hal is halogen, R¹′ is acyl, thioacyl, a group R¹⁵VCO—, or agroup R¹⁶R¹⁷NCO— or R¹⁶R¹⁷NCS— where R¹⁵, V, R¹⁶ and R¹⁷ are aspreviously defined except that neither R¹⁶ nor R¹⁷ may be hydrogen, orwith a lower alkylsulfonyl halogenide, trifluoromethylsulhonylhalogenide or an isocyanate or thioisocyanate of the formula R¹⁶—N═C═Oor R¹⁶—N═C═S wherein R¹⁶ is as previously defined:

[0260] 7) Reacting an anilino derivative of the formula IX:

[0261] wherein one of R²-R⁵ is NHR¹⁴, and R¹⁴ is defined as above andthe other R²-R⁵, X, Y, A, n, m. W, and the dotted line are as previouslydefined, with a reagent of the formula R¹³—L, where L is a leaving groupsuch as halogens mesylate or tosylate and R¹³ is as previously defined,or of the formula R¹³′—hal or R¹³′—OCOR, in which formulas hal ishalogen, R¹³′ is acyl, thioacyl, a group R¹⁵VCO—, or a group R¹⁶R¹⁷NCO—or R¹⁶R¹⁷NCS— where R¹⁵, V, R¹⁶ and R¹⁷ are as previously defined exceptthat neither R¹⁶ nor R¹⁷ may be hydrogen, or with a lower alkylsulfonylhalogenide, trifluoromethylsulhonyl halogenide or an isocyanate orthioisocyanate of the formula R¹⁶—N═C═O or R¹⁶—N═C═S wherein R¹⁶ is aspreviously defined;

[0262] 8) Alkylating a dihydroindole derivative of the Formula X with analkylating derivative of the Formula XI:

[0263] wherein R²-R⁵, X, A, n, m, W, and the dotted line are aspreviously defined, and L is a leaving group such as eg. halogen,mesylate, or tosylate; or

[0264] 9) reducing the carbonyl amide compounds of Formula XII:

[0265] wherein R²-R⁵, X, A, n, W and the dotted line are as previouslydefined and s is m−1 and m is as defined above; whereupon the compoundof Formula I is isolated as the free base or a pharmaceuticallyacceptable acid addition salt thereof.

[0266] The reaction in Methods 6) and 7) are conveniently performed atlow temperature (eg. below room temperature) in an inert solve-,t suchas acetone, dichloromethane, tetrahydrofuran or dimethoxyethane whenreactive carboxylic acid chlorides, isocyanates, or isothiocyanates areused. Formylated amines are prepared from the corresponding amines byreaction in formic acid, with esters of formic acid, or by reaction withmixed formic acid anhydride prepared in situ. Generally, reactiontemperatures are between 0° C. and the boiling point of the formylprecursor compounds.

[0267] The alkylations according to Methods 1) and 8) are generallyperformed by refluxing in a suitable solvent such as acetone, methylisobutyl ketone, tetrahydrofuran, dioxane, ethanol or 2-propanol in thepresence of a base such as triethylamine or potassium carbonate.

[0268] The reductions of double bonds according to Methods 4) and 5) aregenerally performed by catalytic hydrogenation at low pressure (<3 atm.)in a Parr apparatus, or by using reducing agents such as diborane orhydroboric derivatives as produced in situ from NaBH₄ in trifluoroaceticacid in inert solvents such as tetrahydrofuran, dioxane, or diethylether.

[0269] The reductions according to Methods 2) and 9) are generallyperformed by use of LiAlH₄, AlH₃ or diborane in an inert solvent such astetrahydrofuran, dioxane, or diethyl ether at room temperature or at aslightly elevated temperature.

[0270] The halogenation according to Method 3)is generally performed byuse of chlorine, bromine, or N-chlorosuccinimide, N-bromosuccinimide oranother halogen precursor molecule, conveniently in the presence of acatalyst such as Fe ions or a mineral acid.

[0271] The indoles 7-chloro-1H-indole and 6,7-dichloro-1H-indole wereprepared in accordance with the procedure of G. Bartoli et al.,Tetrahedron Left. 1989, 30, 2129-2132. The two piperazinylindoles4-(piperazin-1-yl)-1H-indole and 5-(piperazin-1-yl)-1H-indole have beendescribed in the literature, WO patent publication No. 95/33743 and U.S.Pat. No.5,576,319.

[0272] Synthesis of 3-(piperidin-4-yl)-1H-indoles and3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles have been described in theliterature EP-A1-465398.

[0273] Key intermediates such as 1-indanecarboxylic acid ( V. Asham andW. H. Lirmell, J Chem. Soc. 1954, 4691-4693, Hansen et al. Helv. Chim.Acta 1982, 33, 325-343) and 6-nitro-1-indanecarboxylic acid (G. Kirschet al. Just. Lieb. Ann. Chem. 1976, 10, 1914) were prepared according towell-known literature procedures. (Indan-2-yl)acetic acid,3-(indan-2-yl)propionic acid, 4-(indan-2-yl)butyric acid, and2-(indan-2-yl)ethanol have been described in the literature (Y. Tanakaet al. J. Med. Chem. 1994, 37, 2071-2078).

[0274] Experimental Section

[0275] Melting points were determined on a Büichi SMP-20 apparatus andare not corrected. Mass spectra were obtained on a Quattro MS-MS systemfrom VG Biotech, Fisons Instruments. The MS-MS system was connected toan HP 1050 modular HPLC system. A volume of 20-50 μl of the sample (10μ/ml) dissolved in a mixture of 1% acetic acid in acetonitril/water 1:1was introduced via the autosampler at a flow of 30 μl/min into theElectrospray Source. Spectra were obtained at two standard sets ofoperating conditions. One set to obtain molecular weight information(MH+) (21 eV) and the other set to induce fragmentation patterns (70eV). The background was subtracted. The relative intensities of the ionsare obtained from the fragmentation pattern. When no intensity isindicated for the Molecular Ion (MH+) this ion was only present underthe first set of operating conditions. 1H NMR spectra were recorded ofall novel compounds at 250 MHz on a Bruker AC 250 or at 500 MHz onBruker Avance DRX 500 instrument. Deuterated chloroform (99,8% D) ordimethylsulfoxide (99,9% D) were used as solvents. TMS was used asinternal reference standard. Chemical shift values are expressed inppm-values. The following abbreviations are used for multiplicity of NMRsignals: s=singlet, d=doublet, triplet, q=quartet, qui=quintet,h=heptet, dd=double doublet, dt=double triplet, dq=double quartet,triplet of triplets, m=multiplet. NMR signals corresponding to acidicprotons are generally omitted. Content of water in crystalline compoundswas determined by Karl Fischer titration. Standard workup proceduresrefer to extraction with the indicated organic solvent from properaqueous solutions, drying of combined organic extracts (anhydrous MgSO₄or Na₂SO₄), filtering and evaporation of the solvent in vacuo. Forcolumn chromatography silica gel of type Kieselgel 60, 230-400 mesh ASTMwas used.

EXAMPLE 1

[0276] 1-Indanylmethanol, 1a.

[0277] (intermediate)

[0278] To a suspension of LiAlH₄ (4.7 g) in diethyl ether (200 ml) wasadded dropwise a solution of AlCl₃ in diethyl ether (200 ml). A solutionof 1-indanecarboxylic acid (10 g) (prepared according to the method ofHansen et al. Helv. Chim. Acta 1982, 33, 325-343) in dry tetrahydrofuran(200 ml) was added drop-wise at 10-15° C. The mixture was finallystirred at room temperature for 1.5 hours Excess AlH₃ was destroyed byaddition of concentrated aqueous NaOH solution (25 ml) at 0° C.Precipitated inorganic salts were filtered off and the solventsevaporated in vacuo leaving 6.8 g of the title compound 1a as a viscousoil which was used without further purification.

[0279] The following 1-indanylmethanols were prepared in a similarmanner:

[0280] 6-Bromo-1-indanylmethanol from alane reduction of thecorresponding methyl 6-bromo 1-indanecarboxylic acid ester, isolated asa viscous oil. 1b.

EXAMPLE 2

[0281] 6-Cyano-1-indanylmethanol 2 a.

[0282] (Intermediate)

[0283] To a solution of 6-bromo-1-indanylmethanol (20 g) inN-methyl-2-pyrrolidone (NMP) (380 ml) was added CuCN (79 g). The mixturewas heated at 160° C. for 6 hours. After cooling to 80-90° C. themixture was poured into an aqueous solution (500 ml) of NaCN (4g). Afterstirring for 20 minutes excess CuCN was filtered off. Ethyl acetate (300ml) was added and the organic phase was separated and worked-up. Theremaining oil was dissolved in diethyl ether (300 ml) and washed withsaturated brine (2×100 ml). The organic phase was separated andworked-up according to the general procedure leaving 14.6 g of crudetitle compound 2a as a visceous oil. Column chromatography on silica gel(eluent:ethylacetat/heptane 6:4) afforded pure 2a (8.7 g) which was usedwithout further purification.

EXAMPLE 3

[0284]6-Cyano-1-indanylmethanol methanesulfonate, 3 a.

[0285] (Intermediate)

[0286] To a solution of 6-cyano-1-indanylmethanol 2a (3 g) andtriethylamine (2.8 ml) in dichloromethane (50 ml) was added drop-wise asolution of methansulfonylchloride (1.5 ml) in dichloromethane (25 ml)at 0° C. The mixture was stirred at room temperature for 1 hour. Waterwas added (200 ml) and the organic phase was subsequently separated andworked-up according to the standard procedure above. The remainingcrystalline product was stirred with diethyl ether and filtered off.Yield 2.7 g Mp 62-63° C.

[0287] The following methanesulfonates were prepared in a similarmanner:

[0288] 1-Indanylmethanol methanesulfonate, 3b. Isolated as a viscous oil

[0289] 6-Bromo-1-indanylmethanol methanesulfonate, 3c.

[0290] 6-Nitro-1-indanylmethanol methanesulfonate, 3d

[0291] 6-Chloro-1-indanylmethanol methanesulfonate, 3e

EXAMPLE 4

[0292]3-[1-(1-indanylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole, 4a

[0293] 1-Indanecarboxylic acid chloride (4.5 g), prepared as describedin International Patent Application No WO 9533721-A1 in dichloromethane(25 ml) was added drop-wise at 0-5° C. to a mixture of3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (5 g) (see general methodfor preparation in Guillaume et al. Eur J Med. Chem. 1987, 22, 33-43)and triethylamine (3.8 ml) in THF (50 ml). The resulting mixture wasstirred overnight at room temperature. The mixture was poured intodiluted aqueous NH₄OH (500 ml) and extracted several times withdichloromethane (4×100 ml). The combined organic phases were worked upaccording to the general procedure above. Column chromatography (elutedwith ethyl acetate/heptane 70/30) of the crude product afforded puretitle compound 4 a as a visceous oil (4.7 g) which was used withoutfurther purification.

[0294] In a similar manner was prepared the following amides wereprepared:

[0295] 3-[1-(1-Indanylcarbonyl)piperidin-4-yl]-1H-indole 4b

[0296] isolated as an oil.

[0297]6-Chloro-3-1-(7-methoxy-1-indanylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,4c.

[0298] From compound 23a and6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.

[0299]3-[1-(6-Methoxy-1-indanylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole4d.

[0300] From compound 23b and3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.

EXAMPLE 5

[0301] 3-[1-(1-Indanylmethyl)-1,2,3,6-tetrahydropyridin-4yl]-1H-indole,5a

[0302] To a solution of LiAlH₄ (1.6 g) in dry THF (100 ml) kept at 0° C.was added drop-wise a solution of3-[1-(1-indanylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole 4a(4.7 g) in dry THF (200 ml). The mixture was left stirring over-night atroom temperature. Excess LiAlH₄ was destroyed by cautiously adding 10%water in THF. The precipitated inorganic salts were filtered off. Thesolvents were evaporated leaving crude title compound (5.2 g).Recrystallization from 2-propanol afforded 2.8 g of pure 5a. Mp168-170°0C. ¹H NMR (CDCl₃): δ 1.85-2.00 (m, 1H); 2.30-2.45 (m, 1H); 2.60(dd, 1H); 2.60-2.70 (m, 2H); 2.70-3.00 (m, 5H); 3.30 (broad t, 2H); 3.45(quin, 1H); 6.25 (broad t, 1H); 7.10-7.25 (m, 6H); 7.30-7.40 (m, 2H);7.90 (d, 1H); 8.10 (broad s, 1H). MS m/z (%): 329 (ME+, 2%), 160 (10%),131 (100%), 91 (19%).

[0303] In a similar manner the following indanemethylamines wereprepared

[0304] 3-[1-(1-Indanylmethyl)piperindin-4-yl]-1H-indole fumarate, 5b.Prepared from compound 4b.

[0305] Mp 216-218° C. ¹H NMR (DMSO-d₆): δ 1.70-2.00 (m, 5H); 2.20-2.35(m, 1H); 2.40-2.50 (m, 2i), 2.65 (dd, 1H); 2.80-3.00 (m, 4H); 3.20(broad t, 2H); 3.45 (quin, 1H); 6.60 (s, 2H); 6.95 (t, 1H); 7.05 (t,1H); 7.15-7.30 (m, 4H); 7.30-7.40 (m, 2H); 7.60 (d, 1H); 10.80 (s, 1H).MS m/z (%): 331 (MH+, 15%),214 (18%), 131 (100%).

[0306]6-Chloro-3-[1-(7-methoxyindan-1-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,5c.

[0307] Prepared from compound 4c. Mp 177-178° C. ¹H NMR (CDCl₃) δ2.15-2.30 (m, 2H), 2.45 (t, 1H), 2.55 (broad s, 2H), 2.65-2.70 (m, 1H),2.75-2.90 (m, 2H), 2.90-3.00 (m, 1H), 3.00-3.10 (m, 1H), 3.25 (d, 1H),3.40 (d, 1H), 3.60-3.65 (m, 1H), 3.85 (s, 3H), 6.20 (broad s, 1H), 6.70(d, 1H), 6.85 (d, 1H), 7.05-7.20 (m, 3H), 7.30 (s, 1H), 7.80 (d, 1H),8.25 (broad s, 1H). MS m/z (%): 393 (MH+) 190 (25%), 161 (100%).

[0308]3-[1-(6-methoxyindan-1-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indoleoxalate, 5d.

[0309] Prepared form compound 4d. Mp 118-120° C. ¹H NMR (DMSO-d₆) δ1.90-2.00 (m, 1H), 2.35-2.45 (m, 1H), 2.70-2.95 (m, 4H), 3.15 (t, 1H),3.45 (broad s, 2H), 3.50-3.65 (m, 2H), 3.75 (s, 3H), 3.95 (broad s, 2H),6.20 (broad s, 1H), 6.75 (d, 1H), 6.95 (s, 1H), 7.10 (t, 1H), 7.10-7.20(m, 2H), 7.45 (d, 1H), 7.55 (s, 1H), 7.85 (d, 1H), 11.35 (broad s, 1H).MS m/z (%): 359 (MH+, 6%) 190 (15%), 161 (100%), 147 (74%).

EXAMPLE 6

[0310]6-Chloro-3-[1-(6-cyano-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,6a

[0311] A mixture of 6-cyano-1-indanylmethanol methanesulfonate, 3a (1.3g), 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (2.5 g), andpotassium carbonate (1.9 g) in NMP (50 ml) was heated at 110° C. for 5hours. After cooling to room temperature the mixture was poured intowater (500 ml) and ethyl acetate (100 ml) was added. Work up accordingto the general procedure above afforded 4.7 g of impure product. Columnchromatography (eluted with ethyl acetate/heptane/ethanol/triethylamine30/60/10/4) afforded 1.5 g of pure compound. The crystalline product wasstirred with diethyl ether and subsequently filtered. Mp 175-177° C. ¹HNMR (CDCl₃): δ 1.85-2.00 (m, 1H); 2.35-2.45 (m, 1H); 2.50-3.00 (m, 8H):3.30 (broad t, 2H). 3.45 (quin, 1H); 6.15 (broad t. 1H); 7.05 (dd, 1H);7.20-7.50 (m, 4H); 7.70-7.85 (m, 2H); 10.60 (broad s, 1H). MS m/z (%):388 (MH+, 4%), 185 (40%), 156 (100%), 129 (53%).

[0312] In a similar manner were prepared the followingindanemethylamines

[0313] 6-Chloro-3-[1-(6-cyano-1-indanylmethyl)piperidin-4-yl]-1H-indole,hemifumarate, 6b

[0314] Prepared from compound 3a. Mp 175-177° C. ¹H NMR (DMSO-d₆): δ1.65-2.00 (m, 5H); 2.20-2.30 (m, 3H); 2.40-2.50 (m, 2H); 2.65 (dd, 1H);2.70-3.15 (m, 4H); 3.45 (quin, 1H); 6.60 (s, 1H); 6.95 (dd, 1H); 7.15(d, 1H); 7.35 (d, 1H); 7.45 (d, 1H); 7.55-7.65 (m, 2H); 7.80 (s, 1H),10.95 (s, 1H). MS m/z (%): 392 (17%), 390 (MH+, 47%), 239 (100%), 156(69%).

[0315]6-Chloro-3-[1-(4-acetylamino-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,6c.

[0316] Mp 189-190° C. ¹H NMR (DMSO-d₆): δ 1.65-1.90 (m, 1H); 2.05 (s,3H1); 2.10-2.30 (m, 1H); 2.40-2.95 (m, 8H); 3.20 (broad s, 2H); 3.45(quin, 1H); 6.15 (broad t, 1H); 7.00-7.15 (m, 3H); 7.40-7.50 (m, 3H);7.85 (d, 1H); 9.25 (s, 1H); 11.25 (s, 1H). MS m/z (%): 420 (MH+, 16%),217 (65%), 188 (100%), 146 (57%).

[0317] The last mentioned compound was prepared from4-Acetylamino-1-indanemethanol methanesulfonate which again was obtainedfrom 4-Amino-1-indanemethanol as follows:

[0318] 4-Amino-1-indanemethanol

[0319] A mixture of 4-nitro-1-indanecarboxylic acid and6-nitro-1-indanecarboxylic acid were obtained according to the procedurefor nitration of 1-indanecarboxylic acid by G. Kirsch et al. Just. Lieb.Ann. Chem. 1976, 10, 1914. This mixture was reduced with alane accordingto the method in Example 1). A mixture (21.9 g) of the thus obtained4-nitro- and 6-nitroindane-1-methanol was dissolved in glacial aceticacid (600 ml) and 5% Pd on carbon black (11 g) was added. The mixturewas hydrogenated in a Parr apparatus below 2 ato for 2.5 hours. Thecatalyst was filtered off and the solvent evaporated in vacuo. Water(500 ml) and ethyl acetate (200 ml) kept at 0° C. were added. Ph wasadjusted >10 by adding aqueous NaOH solution. The organic phase wasseparated and worked up according to the general procedure above. The 4-and 6-anilinoisomers were separated by column chromatography on silicagel (eluted with ethyl acetate/heptane 60/40). Yield of the4-amino-1-indanemethanol as a visceous oil: 3.6 g.

[0320]4-Acetylamino-1-indanemethanol methanesulfonate,

[0321] To a mixture of 4-amino-1-Indanemethanol (3.4 g) andtriethylamine (8.1 ml) in dichloromethane (150 ml) was added drop-wiseat −30° C. acetylchloride (1.4 ml) in dichloromethane (20 ml). Themixture was stirred for another hour while the temperature was allowedto raise to 0° C. A solution of methanesulfonylchlorid (1.7 ml) indichloromethane (20 ml) was added slowly below 0° C.

[0322] Finally the mixture was allowed to heat to room temperature.Water (200 ml) and dichloromethane (50 ml) were added. The organic phasewas separated and worked up as above yielding the title metanesulfonateas an oil (6.7 g as crude product).

[0323]6-Chloro-3-[1-(5-acetylamino-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indolehemifumarate, 6d.

[0324] Mp 241-242° C., ¹H NMR (DMSO-d₆) δ 1.70-1.90 (1H, m), 2.00 (3H,s), 2.11-2.30 (1H, m), 2.40-2.60 (2H, m), 2.60-2.95 (5H, m), 3.20 (2H,bs), 3.25-3.40 (2H, m), 6.10 (1H, s), 7.05 (1H, d), 7.25 (2H, s), 7.40(1H, s), 7.45 (1H, d), 7.55 (1H, s), 7.85 (2, d), 9.80 (1H, bs), 11.25(1H, bs). MS m/z (%): 420 (MH+, 5 %), 188 (100%), 146 (100%), 217 (31%),147 (27%).

[0325] The last mentioned compound was prepared from5-Acetylamino-1-indanemethanol methanesulfonate which again was preparedfrom 6-chloro-5-nitro-1-indanecarboxylic acid (G. Kirch et al, Lieb.Ann. Chem., 1976, 10, 1914), in a similar manner as the above describedsynthesis of 4-Acetylamino-1-indanemethanol methanesulfonate.

[0326]6-Chloro-3-[1-(6-bromo-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,6e.

[0327] Prepared from compound 3c. Mp 153-155° C. ¹H NMR (CDCl₃) δ1.85-1.95 (m, 1H), 2.30-2.40 (m, 1H), 2.50-2.65 (m, 3H), 2.65-2.90 (m,5H), 3.25 (broad s, 2H), 3.45 (p, 1H), 6.20 (broad s, 1H), 7.00-7.20 (m,3H), 7.25 (s, 1H), 7.30 (d, 1H), 7.50 (s, 1H), 7.80 (d, 1H), 8.15 (broads, 1H). MS m/z (%): 443 (MH+, 7%), 441 (MH+, 7%), 240 (50%), 238 (49%),211 (59%), 209 (62%), 130 (100%).

[0328]5-Fluoro-3-1-(6-nitro-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indolehemifumarate, 6f.

[0329] Prepared from compound 3d. Mp >300° C. ¹H NMR (DMSO-d₆) δ1.85-1.95 (m, 1H), 2.30-2.40 (m, 1H), 2.50-2.60 (m, 3H), 2.70-3.05 (m,5H), 3.25 (broad dd, 2H), 3.50 (p, 1H), 6.10 (broad s, 1H), 6.60 (s,1H), 6.95 (t, 1H), 7.35 (dd, 1H), 7.45-7.50 (m, 2H), 7.55 (d, 1H), 8.05(d, 1H), 8.25 (s, 1H), 11.25 (s, 1H). MS m/z(%): 392 (MH+, 5%), 205(29%), 176 (46%), 130 (100%).

[0330] 5-Fluoro-3-11-(6-nitro-1-indanylmethyl)-piperidin-4-yl]-1H-indole6g.

[0331] Mp>300° C. ¹H NMR (CDCl₃) δ 1.75-1.95 (m, 3H), 2.00-2.10 (m, 2H),2.25 (t, 211), 2.30-2.40 (m, 1H), 2.45-2.65 (m, 2H), 2.75 (tt, 1H),2.85-3.15 (m, 4H), 3.45 (p, 1H), 6.95 (dt, 1H), 7.15 (d, 1H), 7.20-7.30(m, 3H), 7.95 (broad s, 1H), 8.05 (dd, 1H), 8.30 (s, 1H). MS m/z (%):394 (MH+, 58%), 259 (95%), 176 (58%), 130 (57%), 98 (51%), 84 (100%).

[0332]3-[1-(6-Chloro-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-5-fluoro-1H-indolehemifumarate, 6h.

[0333] Prepared from compound 3e. Mp 211-213° C. ¹H NMR (DMSO-d₆) δ1.75-1.85 (m, 1H), 2.20-2.30 (m, 1H), 2.55-2.65 (m, 3H), 2.75-2.90 (mi,5H), 3.25 (broad s, 2H), 345 (p, 1H), 6.10 (broad s, 1H), 6.60 (s, I H),6.95 (t, 1H), 7.20 (d, 1H), 7.25 (d, 1H), 7.35 (dd, 1H), 7.40 (s. 1H),7.45 (s, 1H), 7.55 (D, 1H), 11.25 (S, 1H). MS m/z (%). 381 (MH+, 5%),167 (32%), 165 100%), 130 (53%).

[0334]3-[1-(6-Chloro-1-indanylmethyl)-piperidin-4-yl]-5-fluoro-1H-indolefumarate, 6i.

[0335] Mp 214-216° C. ¹H NMR (DMSO-d₆) δ1.75-1.85 (m, 3H), 2.00 (d, 2H),2.25-2.30 (m, 1H), 2.40 (t, 2H), 2.60 (t, 1H), 2.75-2.90 (m, 4H), 3.20(broad t, 2H), 3.45 (p, 1H), 6.60 (s, 2H), 6.90 (t, 1H), 7.15-7.25 (m,3H), 7.30-7.35 (m, 2H), 7.45 (s, 1H), 10.90 (s, 1H). MS m/z (%): 383(MH+, 16%), 248 (19%), 167 (31%), 165 (100%).

EXAMPLE 7

[0336]6-Chloro-3-[1-[2-indan-1-yl)methylcarbonyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,7a.

[0337] A solution of indan-1-acetic acid (Anderson, A. G. et al; J. Org.Chem. 1989, 38(8), 1439-1444) (7.0 g, 39.7 mmol), DMF (3 ml) and SOCl₂(17.5 g, 147 mmol) in CH₂Cl₂ (250 ml) was refluxed for 4 h. The mixturewas evaporated and re-evaporated from toluene to give the correspondingacid chloride. To a solution of6-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (EP Patentpublication No 465398-A1) (9.2 g, 39.7 mmol) and TEA (10 ml) in THF (120ml) was added drop-wise over 20 min. a solution of the acid chloride inTHF (120 ml). The mixture was stirred for 1.5 h and evaporated. H₂O (50ml) was added to the remanence and the mixture was extracted with CH₂Cl₂(2×150 ml). After washing with H₂O (20 ml) and brine (20 ml), thecombined organic phases were dried with MgSO₄ and evaporated. Theproduct was purified by column chromatography (EtOAc: heptane=1:1) togive the title compound 7a (7.8 g, 50%): ¹H NMR (DMSO-d₆) δ 1.55-1.72(1H, m), 2.20-2.60 (3H, m), 2.69-2.95 (4H, m), 3.48-3.58 (1H, m),3.61-3.81 (2H, m), 4.18 (2H, bs), 6.12 (1H, d), 7.05 (1H, dd), 7.08-7.16(2H, m), 7.17-7.31 (2H, m). 7.42 (1H, d), 7.49 (1H, dd), 7.81 (1H, dd),11.31 (1H, bs).

EXAMPLE 8

[0338]6-Chloro-3-[1-[2-(indan-1-yl)ethyl]-1,2,3,6-tetrahydropyridine-4-yl]-1H-indole8a.

[0339] To a suspension of LiAlH₄ (2.3 g, 60.0 mmol) in THF (150 ml) wasadded drop-wise over 20 mm. to a solution of6-Chloro-3-[1-[2-(indane-1-yl)methylcarbonyl]-1,2,3,6-tetrahydropyridine-4-yl]-1H-indole,7a (7.8 g. 20.0 mmol) in THF (150 ml). The mixture was refluxed for 1.5h and then cooled to 10-15° C. After drop-wise addition of H₂O (3 ml),aqueous (15%) NaOH (3ml) and H₂O (12 ml), the solution was filtered andevaporated to almost dryness. The remanence was dissolved in CH₂Cl₂ andafter drying with MgSO₄, the solution was evaporated to give the titlecompound 8a (5.7g, 77%): mp 181-183° C., ¹H NMR (DMSO-d₆) δ1.45-1.70(2H, m), 1.95-2.15 (1H, m), 2.20-2.35 (1H, m), 2.45-2.60 (4H, m)2.60-2.95 (4H, m), 3.00-3.20 (3H, m), 6.10-6.15 (1H, m), 7.00 (1H, dd),7.10-7.25 (4H, m), 7.40 (2H, d), 7.80 (1H, d), 11.25 (1H, bs). MS m/z(%): 377 (MH+, 38 %), 131 (100%).

[0340] The following compounds were prepared analogously according theprocedures described in example 7 and 8:

[0341]5-Fluoro-3-[1-[2-(indan-1-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,8b. Mp 172-176° C., ¹H NMR (CDCl₃) δ 1.70-1.80 (m, 2H), 2.15-2.25 (m,1H), 2.30-2.40 (m, 1H), 2.60-2.70 (m, 4H), 2.75-2.85 (m, 2H), 2.85-2.90(m, 1H), 2.90-3.00 (m, 1H), 3.20-3.30 (m, 3H), 6.10 (broad s, 1H), 6.95(t, 1H), 7.15-7.30 (m, 6H), 7.50 (d. 1H), 8.15 (broad s, 1H). MS m/z(%): 361 (MH+, 67%), 174 (74%), 131 (100%).

[0342] By hydrogenation of compound 8b at 3 atm in acetic acid usingPtO₂ as catalyst in a Parr apparatus5-fluoro-3-[1-[2-(indan-1-yl)ethyl]-piperidin-4-yl]-1H-indole, oxalate8c was obtained. Mp 107-115. ¹H NMR (DMSO-d₆) δ1.55-1.85 (m, 2H),1.90-2.00 (m, 2H), 2.10 (broad d, 2H), 2.20-2.30 (m, 2H), 2.75-2.85 (m,1H), 2.85-2.95 (m, 1H), 3.00-3.20 (m, 6H), 3.55 (broad s, 2H), 6.90 (t,1H), 7.15-7.20 (m, 2H), 7.20-7.25 (m, 2H), 7.25 (d, 1H), 7.30-7.40 (m,1H), 7.35 (d, 1H), 11.00 (s, 1H). MS m/z (%). 363 (MH+, 9%), 117 (10%),98 (100%).

[0343]5-Fluoro-3-[1-[4-(indan-1-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,8d.

[0344] Mp 172-176° C., ¹H NMR (CDCl₃) δ 1.40-1.70 (m, 6H), 1.85-1.95 (m,1H) 2.25-2.35 (m, 1H), 2.50 (t, 2H), 2.60 (broad s, 2H), 2.70 (t, 2H),2.80-2.90 (m, 1H), 2.90-3.00 (m, 1H), 3.05-3.15 (m, 1H), 3.25 (broad s,2H), 6.10 (broad s, 1H), 6.95 (t, 1H), 7.10-7.30 (m, 6H), 7.50 (d, 1H),8.10 (s, 1H). MS m/z(%): 389 (MH+, 9%), 202 (100%), 171 (44%), 129(73%).

[0345] By hydrogenation of compound 8d at 3 atm in acetic acid usingPtO₂ as catalyst in a Parr apparatus5-fluoro-3-[1-[4-(indan-1-yl)butan-1-yl]-piperidin-4-yl]-1H-indole 8ewas obtained. Mp 83-86° C., ¹H NMR (CDCl₃) δ 1.25-1.90 (m, 9H),1.95-2.10 (m, 4H), 2.20-2.30 (m, 1H), 2.35-2.45 (m. 2H), 2.70-2.90 (m,3H), 3.05-3.15 (m, 3H), 6.90 (t, 1H), 6.95 (s, 1H). 7.10-7.30 (m. 6H),8.15 (s, 1H). MS m/z(%): 391 (MH+, 61%), 256 (78%), 98 (100%).

[0346]6-Chloro-3-[1-4-(indan-1-yl)butan-1-yl)-piperidin-4-yl]-1H-indole,oxalate 8f.

[0347] Mp 206-208° C. ¹H NMR (DMSO-d₆) δ1.40-1.50 (m, 3H), 1.60-1.65 (m,1H), 1.65-1.70 (m, 2H), 1.80-1.90 (m, 1H), 1.95-2.10 (m, 4H),2.20-2.30(m 1H), 2.70-2.80 (m, 1H), 2.80-2.90 (m, 1H), 2.95-3.10 (m, 6H), 3.55(broad d, 2H), 6.95 (d, 1H), 7.10-7.30 (m, 5H), 7.40 (s, 1H), 7.65 (d,1H), 11.10 (s, 1H). MS m/z (%): 407 (MH+, 69%), 256 (100%), 117 (39%),98 (51%).

[0348]6-Chloro-3-[1-[3-(indan-1-yl)propan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,⁸g.

[0349] Mp 198-200° C., ¹H NMR (CHCl₃-d) δ1.40-1.55 (1H, m), 1.60-1.80(3H, m), 1.75-1.95 (1H, m), 2.20-2.40 (1H, m), 2.45-2.60 (4H, m), 2.70(2H, t), 2.80-3.00 (2H, m), 3.10-3.15 (1H, m), 3.20-3.25 (2H, m), 6.15(1H, s), 7.05-7.30 (6H, m), 7.30 (1H, d), 7.80 (1H, d), 8.25 (1H, bs).MS m/z (%): 391 (MH+, 5%), 157 (100%), 129 (76%), 188 (56%).

[0350]6-Chloro-3-[1-[4-(indane-1-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl-1H-indoleoxalate, 8h.

[0351] Mp 191-192° C., ¹H NMR (DMSO-d₆) δ1.40-1.50 (3H, m), 1.60-1.65(1H, m), 1.70-1.80 (2H, m), 1.80-1.90 (1H, m), 2.30-2.25 (1H, m),2.25-2.30 (3H, m), 2.30-2.90 (1H, m), 3.05-3.20 (3H, m), 3.35 (2H, bs),3.80 (2H, bs), 6.10 (1H, s), 7.10 (1H, d), 7.10 (2H, m), 7.20 (2H, m),7.45 (1H, s), 7.55 (1H, s), 7.80 (1H, d). MS m/z (%): 405 (MH+, 6 %),202 (100%), 129 (54%), 171 (36%).

[0352] The synthesis of 3-(indan-1-yl)propanoic and acid4-(indan-1-yl)butanoic acid is described by A. Mukhopadhyay et al. J.Indian Chem. Soc. 1985, 62(9), 690-2.

EXAMPLE 9

[0353] Indane-2-carboxylic Acid 9a.

[0354] (Intermediate)

[0355] A solution of indane-2,2-dicarboxylic acid (17 g. Baeyer andPerkin, Ber. 1884, 17, 122) in NMP (200 ml) was heated to 150° C. for 1hour. After cooling to 20° C. the solution was poured in water (300 ml)and concentrated hydrochloric acid was added to pH=1. Conventional workup with ether gave the title product (4.7 g). Mp 132-33° C. (fromether).

EXAMPLE 10

[0356]6-Chloro-3-[1-[(indan-2-yl)carbonyl]-1,2,3,6-tetrahydopyrid-4-yl]-1H-indole,10a

[0357] To a solution of 9a (2.1 g) in dichloromethane (200 ml) was addedthionyl chloride (1.4 ml) and DMF (2 ml). After reflux for 2.5 hours,the mixture was concentrated in vacuo and dissolved in DMF (50 ml). Thesolution was added drop-wise to an ice-cooled solution of6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (EP Patentpublication No 465398-A1) (3.0 g) in DMF (200 ml) and triethylamine (9ml). The reaction mixture was left with stirring at room temperature for16 hours and then poured into a saturated solution of sodium chloride(500 ml). Conventional work up with ethyl acetate gave the title product(4.7 g) which was sufficiently pure for further reaction In a similarmanner the following compounds were prepared:

[0358]3-[1-[(Indan-2-yl)carbonyl]-1,2,3,6-tetrahydopyrid-4-yl]-1H-indole, 10b.

[0359] Prepared from compound 9a and3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.

[0360]7-Chloro-3-[1-[(indan-2-yl)carbonyl]-1,2,3,6-tetrahydopyrid-4-yl]-1H-indole,10c.

[0361] Prepared from 9a and7-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.

[0362]6,7-Dihloro-3-[1-[(indan-2-yl)carbonyl]-1,2,3,6-tetrahydopyrid-4-yl-1H-indole,10d.

[0363] Prepared from 9a and6,7-dichloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.

[0364]3-[1-[(Indan-2-yl)carbonyl]-1,2,3,6-tetrahydopyrid-4-yl]-5,6-methylenedioxy-1H-indole,10e.

[0365] Prepared from 9a and5,6-methylenedioxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.

[0366] 5-[4-[(Indan-2-yl)carbonylipiperazin-1-yl]-1H-indole, 10f.

[0367] Prepared from 9a and 5-(piperazinyl)-1H-indole.

[0368]6-Chloro-3-[1-[2-(indan-2-yl)methylcarbonyl]-1,2,3,6-tetrahydopyrid-4-yl]-1H-indole,10g.

[0369] From 2-(indan-2-yl)acetic acid and6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.

[0370]6-Chloro-3-[1-[3-(indan-2-yl)ethylcarbonyl]-1,2,3,6-tetrahydopyrid-4-yl]-1H-indole,10h. From 3-(indan-2-yl)propionic acid6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.

[0371]6-Chloro-3[-1-[4-(indan-2-yl)propylcarbonyl-1,2,3,6-tetrahydopyrid4-yl]-1H-indole,10i.

[0372] From 4-(indan-2-yl)butyric acid6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.

EXAMPLE 11

[0373]6-Chloro-3-[1-(indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,oxalate11a.

[0374] A solution of of 10a (3.2 g) in THF (100 ml) was added to acooled suspension of LiAlH4 (0.9 g) in THF (150 ml) at 5° C. The mixturewas stirred at room temperature for 4 hours. The mixture was then cooledon ice and after drop-wise addition of water (1.5 ml), 15% NaOH (1 ml),and water (3.5 ml) it was filtered and evaporated in vacuo. The residuewas dissolved in CH₂Cl₂ and worked up in a conventional manner yieldingyellow crystals (3.2 g) which were recrystallized from actone giving 1.1g, mp 161-63° C. The title oxalate was crystallized from acetone. Yield0.45 g, mp. 203-5° C. ¹H NMR (DMSO-d₆) δ2.65-2.80 (m, 5H), 2.80-2.95 (m,1H), 2.95-3.30 (m, 5H), 3.65 (s, 2H), 6.15 (s, 1H), 7.05 (dd, 1H),7.10-7.15 (m, 2H), 7.15-7.25 (m, 2H), 7.45 (d, 1H), 7.55 (d, 1H), 7.85(d, 1H), 11.45 (s, 1H). MS m/z (%): 363 (MH+, 100%), 245 (17%), 230(20%).

[0375] In a similar manner the following compounds were prepared:

[0376] 3-[1-(Indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole 11b.

[0377] Prepared from 10b. Mp 156-157° C. ¹H NMR (DMSO-d₆) δ 2.40 (d,2H), 2.45-2.85 (m, 7H), 2.90-3.10 (m, 2H), 3.15 (d, 2H), 6.15 (s, 1H),6.95-7.25 (m, 6H), 7.30-7.40 (m, 2H), 7.80 (d, 1H), 11.10 (s, 1H). MSm/z (%): 329 (MH+, 84%), 160 (87%), 131 (100%).

[0378]7-Chloro-3-[1-(indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,oxalate 11c.

[0379] Prepared from 10c. Mp 135-136° C. ¹H NMR (DMSO-d₆) δ 2.70-3.05(m, 5H), 3.05-3.20 (m, 2H), 3.30 (d, 2H), 3.40 (t, 2H), 3.90 (s, 2H),6.20 (s, 1H), 7.05-7.30 (m, 6H), 7.60 (d, 1H), 7.85 (d, 1H), 11.75 (s,1H). MS m/z (%): 365, 363 (MH+, 46%, 81%), 160 (100%), 131 (53%), 98(81%).

[0380]6,7-Dichloro-3-[1-(indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,11d .

[0381] Prepared form 10d. Mp 151-152° C. ¹H NMR (CDCl₃) δ 2.45-2.65 (m,4H), 2.65-2.90 (m, 5H), 3.00-3.20 (m, 2H), 3.20-3.30 (m, 2H), 6.15(broad s, 1H), 7.05-7.30 (m, 6H), 7.70 (d, 1H), 8.35 (broad s, 1H). 399,397 (MH+, 33%, 53%), 160 (100%), 131 (24%).

[0382]3-[1-(Indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-5,6-methylenedioxy-1H-indole,11e.

[0383] Prepared from 10e. Mp 192-193° C. ¹H NMR (DMSO-d₆) δ2.40 (d, 2H),2.45-2.55 (m, 2H), 2.55-2.80 (m, 5H), 2.95-3.05 (m, 2H), 3.15 (s, 2H),5.95 (s, 2H), 6.00 (s, 1H), 6.90 (s, 1H), 7.05-7.15 (m, 2H), 7.15-7.20(m, 3H), 7.25 (s, 1H), 11.90 (s. 1H). MS m/z (%): 373 (MH+, 100%), 160(100%), 131 (73%), 114 (80%).

[0384] 5-[4-(Indan-2-yl)methylpiperazin-1-yl]-1H-indole, dihydrochloride11f.

[0385] Prepared form 10f. Mp 263-265° C. ¹H NMR (DMSO-d₆) δ 2.80-2.90(m, 2H), 2.90-3.05 (m, 1H), 3.05-3.25 (m, 2H), 3.40 (d, 2H), 3.45-3.95(m, 8H), 6.45 (s, 1H), 7.05-7.25 (m, 5H), 7.35-7.65 (m. 3H), 11.25 (s,1H). MS m/z (%): 332 (MH+, 31%), 159 (100%), 131 (72%).

[0386]6-Chloro-3-[1-[2-(indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,11g.

[0387] Prepared form 10g. Mp 217-218° C. ¹H NMR (DMSO-d₆) δ 1.70 (q,2H), 2.35-2.70 (m, 9H), 2.90-3.20 (m, 4H), 6.10 (broad s, 1H), 6.95-7.25(m, 5H), 7.40 (d, 2H), 7.80 (d, 1H), 11.25 (broad S, 1H) ). MS m/z (%):379, 377 (MH+, 7%, 16%), 174 (93%), 143 (100%).

[0388]6-Chloro-3-[1-[3-(indan-2-yl)propan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,11h

[0389] Prepared form 10h. Mp 176-177° C. ¹H NMR (DMSO-d₆) δ 1.40-1.70(m, 4H), 2.30-2.70 (m, 9H), 2.90-3.15 (m, 4H), 6.10 (broad s, 1H),6.95-7.25 (in, 5H), 7.40 (d, 2H), 7.80 (d, 1H), 11.25 (broad s, 1H). MSm/z (%): 391 (MH+, 6%), 188 (100%), 129 (47%).

[0390]6-Chloro-3-[1-[4-(indan-2-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,11i

[0391] Prepared from 10i. Mp 211-214° C. ¹H NMR (DMSO-d₆) δ 1.30-1.65(in, 6H), 2.25-2.70 (m, 9H), 2.90-3.15 (m, 4H), 6.10 (broad s, 1H),6.95-7.25 (in, 5H), 7.40 (d, 2H), 7.80 (d, 1H), 11.25 (broad s, 1H). MSm/z (%): 407, 405 (MH+, 4%, 10%), 202 (100%), 129 (93%).

[0392] With compound 40a as starting material following the proceduresin Examples 10 and 11 the following compound was prepared:

[0393] 6-chloro-3-[1-[(4-(2-Propyl)oxyindan-2-yl)methylpiperidin-4yl]-1H-indole,oxalate, 11j,

[0394] Mp 119-126° C. ¹H NMR (DMSO-d₆): δ 1.26 (3H, d). 1.27 (3H, d),1.95-2.2 (4H, m), 2.60 (1H, dd), 2.74 (1H, dd), 2.91 (1H, quin), 3.0-3.2(5H, m), 3.2-3.3 (2H, m), 3.5-3.7 (2H, m), 4.57 (1H, h), 6.77 (2H, t),7.0 (1H, dd), 7.09 (1H, t), 7.20 (1H, s), 7.41 (1H, s), 7.66 (1H, d). MSm/z (%): 423 (MH+, 59%), 249 (21%), 147 (20%), 98 (100%).

[0395]5-Fluoro-3-[1-[(4-(2-propyl)oxyindan-2-yl)methyl]piperidin-4-yl]-1H-indole,oxalate, 11k,

[0396] mp 181-189° C. ¹H NMR (DMSO-d₆): d 1.26 (311, d), 1.26 (3H, d),2.61 (1H, dd), 2.74 (1H, dd), 2.7-2.8 (2H, m), 2.92 (1H, h), 3.0-3.2(2H, m), 3.15-3.3 (2H, m), 3.3-3.45 (2H, m). 3.7-3.9 (2H, m), 4.57 (1H,h), 6.11 (1H, s), 6.76 (1H, d), 6.79 (1H, d), 6.99 (1H, dt), 7.42 (1H,dd), 7.5-7.65 (2H, m). MS m/z (%): 405 (MH+, 7%), 231 (4%), 147 (5%), 98(9%). 44 (100%).

[0397] With compound 40b as starting material following the proceduresin Examples 10 and 11 the following compound was prepared:

[0398]6-Chloro-3-[1-[(5,6-dimethoxyindan-2-yl)methyl]piperidin-4-yl]-1H-indole,11l.

[0399] mp 68-79° C. ¹H NMR (DMSO-d₆): d 1.68 (2H. dq), 1.91 (2H, dd),2.06 (2H, dt), 2.31 (2H. d), 2.58 (2H, dd). 2.65-2.77 (2H, m), 291 (1H,dd), 3.70 (6 H, s), 680 (2H, s), 6.96 (1H, dd), 7.15 (1H, d), 736 (1H,d), 7.54 (1H, d). 10.91 (1H, s). MS m/z (%). 425 (MH+, 7%), 249 (11%),191 (16%), 98 (100%)

EXAMPLE 12

[0400] 4-Methyl-1-indanone-3-carboxylic acid, 12a.

[0401] (Intermediate)

[0402] To a mixture of o-tolualdehyde (500 g), ethyl cyanoacetate (445g) and ethanol (500 ml) was added piperidine (16 ml). After azeotropedestillation (200 ml) more ethanol (200 ml) was added, and the mixturewas refluxed for 2 hours. The solution was cooled to 40° C., and asolution of NaCN (225 g) in water (300 ml) was added over 20 minutes.The mixture was stirred for one hour and was then left for 16 hours atroom temperature. Concentrated HCl (5 l) was added slowly and thenwater/ethanol was destined off until the temperature reached 100° C. Themixture was then refluxed for 4 hours and then stirred at roomtemperature for 16 hours. The mixture was filtered, and the crystalswere washed with water. The crystals were dissolved in 4 M NaOH (3 l)and filtrated. Then pH was adjusted to 1 with concentrated hydrochloricacid, and the crystals were filtered off and dried yielding 610 g whichwas dissolved in thionyl chloride (2 l). DMF (10 ml) was added and thesolution was refluxed for 2.5 hours and evaporated in vacuo. The residuewas dissolved in CH₂Cl₂ (1.2 l) and was added during 1 hour to a cooledmixture of AlCl₃ (600 g) in CH₂Cl₂ (4 l) at 0-5° C. The mixture wasstirred at room temperature for 16 hours and was then poured onice/water (5 l) and concentrated hydrochloric acid (500 ml).Conventional work up gave the crude title product (605 g), which waspurified by column chromatography on silica gel eluted withCH₂Cl₂-ether-acetic acid (50:50:2) giving 236 g of the title product.

EXAMPLE 13

[0403] 7-Methyl-indane-1-carboxylic acid, 13a.

[0404] (Intermediate)

[0405] To a solution of 12a (100 g) in trifluoroacetic acid is addedtrietylsilane (141 g). The mixture was stirred for 72 hours at roomtemperature and was then evaporated in vacuo the residue was dissolvedin ethyl acetate and was extracted with dilute NaOH solution. Theaqueous phase was washed with etyl acetate and was then acidified withconcentrated hydrochloric acid. Conventional work up with ethyl acetategave 80.4 g of crude product. Purification on silica gel eluted withethyl acetate-heptane-acetic acid gave the title compound (76.6 g).

EXAMPLE 14

[0406] 3,6,7,8-Tetrahydrocyclopent[e]indole-8-carboxylic acid, 14a

[0407] (Intermediate)

[0408] A solution of 13a (61.2 g) in CH₂Cl₂ (100 ml) was added withstirring during 20 minutes at −50° C. to a mixture of concentratednitric acid (150 ml) and CH₂Cl₂ (40 ml). After stirring at −52° C. for30 minutes the mixture was poured on ice and saturated NaCl solution.Conventional work up with ethyl acetate gave 58.2 g of crude productwhich was purified on silica gel eluted with heptane-ethyl acetate (2:1)to give 45.6 g of product containing 32 % of 5-nitro compound togetherwith other nitro compounds. This product was dissolved in DMF (200 ml)and was heated to 88° C. Tris-(dimethylamino)methane (34.5 g) was added,and the temperature was raised to 123° C., and the mixture was stirredfor 2 hours. The mixture was cooled to 27° C., and a solution ofsemicarbazid, HCl (19 g) in water (200 ml) was added over 8 minutes. Themixture was then stirred for 70 minutes at room temperature. Ethanol(500 ml) was added and iron powder (30 g) and acetic acid (120 ml) wasadded in portions at 50° C. After reflux for 45 minutes the mixture wasfiltered and concentrated to 500 ml in vacuo. Water was added and themixture was worked up with ethyl acetate. The residue was purified onsilica gel eluted with ethyl acetate, giving 5.7 g of the title product.Mp 166-7° C.

EXAMPLE 15

[0409]8-[4-(6-Chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-ylcarbonyl-3,6,7,8-tetrahydrocyclopent[e]indole,15a.

[0410] A solution of 14a (1.4 g).6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1-H-indole (1.6 g),dicyclohexylcarbodiimid (1.9 g), and 4-dimethylaminopyridine (0.1 g) inTHF (100 ml) was stirred for 24 hours at room temperature. The mixturewas filtered and evaporated in vacuo. The residue was purified on silicagel eluted with ethyl acetate-heptane (3:2) giving 1.1 g of the titleproduct as an amorpheous powder.

EXAMPLE 16

[0411]8-14(6-Chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-ylmethyl]-3,6,7,8-tetrahydrocyclopent[e]indole,oxalate 16a.

[0412] The title product was prepared from 15a (1.05 g) as described inExample 3. Yield 0.59 g, mp 155-7° C. ¹H NMR (DMSO-d₆) δ 2.10-2.40 (m,2H), 2.75-2.95 (m, 3H), 2.95-3.25 (m, 2H), 3.35-3.65 (m, 3H), 3.85-4.10(m, 3H), 6.15 (s, 1H), 6.50 (s, 1H), 6.95 (d, 1H), 7.10 (dd, 1H), 7.25(d, 1H), 7.35 (t, 1H), 7.45 (d, 1H), 7.55 (d, 1H), 7.85 (d, 1H), 11.15(s, 1H), 11.55 (s, 1H). MS m/z (%): 402 (MH+, 6%), 170 (96%),156 (100%).

EXAMPLE 17

[0413] 4-nitroindane-2-carboxylic acid chloride, 17a.

[0414] (Intermediate)

[0415] A mixture of 3-nitro-o-xylene (100 g), N-bromosuccinimide, anddibenzoylperoxide (2 g) was heated to reflux for 14 hours. The mixturewas filtered and evaporated in vacuo to give an oil (202 g) which waspurified on silica gel eluted with heptane-ether (10:1) giving 86.4 ofbromo compound which was dissolved in NMP (850 ml) and added to amixture of diethyl malonate (38 g) and 30% Na-methanolate in methanol(105 ml) in NMP (1 l) at 53-60° C. After stirring for 30 minutes at 60°C., the mixture was cooled, poured in cold water, and was worked up witha mixture of ether and ethyl acetate. The residue was purified on silicagel eluted with toluene-ethyl acetate (6:1). The product (25.1 g) wasdissolved in ethanol (250 ml) and THF (50 ml). KOH (27 g) in water (150ml) was added, and the mixture was stirred for 16 hours at roomtemperature. The mixture was concentrated in vacuo to 100 ml and wasfiltered through activated carbon. The filtrate was acidified withconcentrated hydrochloric acid and was worked up with a mixture of etherand ethyl acetate. The residue (16.46 g) was dissolved in NMP (150 ml)and was heated to 145° C. for 10 minutes. The solution was cooled toroom temperature and was poured in saturated NaCl solution. Work up withether/ethyl acetate in a usual manner gave 10.7 g of solid of which 6.0g was dissolved in CH₂Cl₂ (100 ml) and DMF (1 ml). Thionyl chloride (8.4ml) was added, and the solution was refluxed for 16 hours. Evaporationin vacuo gave the semi-crystalline title compound (8,4 g).

[0416] 5-Nitroindane-2-carboxylic acid chloride, 17b.

[0417] A solution of indane-2-carboxylic Acid 9a (18.8 g) in ether (250ml) was added to conc. sulfuric acid (300 ml) (temp.=3-13° C.). To thismixture, a solution of conc. nitric acid (4.4 ml) and conc. sulfuricacid (100 ml) was added (temp.=−1° C.). The mixture was stirred at 2-8°C. for 1 h, poured onto ice, and the aqueous phase was extracted withether. The combined organic extracts were washed with brine, dried(MgSO₄) and evaporated to dryness in vacuo. The residue was crystallizedfrom ether to give 5-nitroindane-2-carboxylic acid (6.0 g). The solidwas dissolved in CH₂Cl₂ (100 ml) and DMF (1 ml). Thionyl chloride (8.4ml) was added, and the solution was boiled under reflux for 5 hours.Evaporation in vacuo gave the title compound (8.6 g).

EXAMPLE 18

[0418]6-Chloro-3-[1-(4-acetylaminoindan-2-yl)methyl-1,2,3,6-tetrahydropyridine-4-yl]-1H-indole,oxalate 18a.

[0419] To a solution of6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1-H-indole (6.4 g) in DMF(250 ml) and triethylamine (14 g) was added a solution of 17a (8.4 g) inDMF (50 ml) during 25 minutes at 3-5° C. The mixture was then stirredfor 45 minutes at room temperature and then poured in water Theprecipitate was filtered off, washed with water and dried to give 9.11 gof solid, which was slurried in refluxing 90% ethanol (450 ml). Ironpowder (9 g) and concentrated hydrochloric acid (1.8 ml) was added inportions during 15 minutes, and the mixture was refluxed for anotherhour. The mixture was concentrated in vacuo, and ice and concentratedammonium hydroxide was added Conventional work up with ethyl acetategave 4.67 g, which was treated with LiAlH₄ as described in Example 11giving 3.2 g solid of which 2 g was dissolved in THF (50 ml) andtriethylamine (3.5 ml). To the ice cooled solution a solution of acetylchloride (0.43 g) in THF (15 ml) was added at 1-4° C. After warm up toroom temperature the mixture was filtered and evaporated in vacuo, andthe residue was purified on silica gel eluted with ethylacetate-ethanol-triethylamine (100:4:4) giving 1.51 g, from which thetitle product was crystallized as the oxalate salt from 2-propanol.Yield 1.29 g, mp 143-4° C. ¹H NMR (DMSO-d₆) δ 2.0 (s, 3H), 2.55-3.00 (m,5H), 3.00-3.15 (m, 4H), 3.25 (broad s, 2H), 3.70 (s, 2H), 6.15 (s, 1H),7.0 (d, 1H), 7.05-7.15 (in, 2H), 7.35 (d, 1H), 7.45 (d, 1H), 7.55 (d,1H), 7.85 (d, 1H), 9.40 (s, 1H), 11.45 (s, 1H). MS m/z (%): 420 (MH+,11%), 217 (87%), 174 (100%).

[0420] In a similar manner the following compound was prepared:

[0421]6-Chloro-3-[1-(4-acetylaminoindan-2-yl)methylpiperidin-4-yl]-1H-indole,oxalate,18b.

[0422] From 6-chloro-3-(piperidine-4-yl)-1H-indole and 17a.

[0423] Mp 153-5° C. ¹H NMR (DMSO-d₆) δ 1.80-2.10 (m, 7H), 2.55-3.15 (m,10H), 3.40 (broad d, 2H), 6.95-7.05 (m, 2H), 7.10 (t, 1H), 7.20 (d, 1H),7.35-7.40 (m, 2H), 7.60 (d, 1H), 9.35 (s, 1H), 11.05 (s, 1H). MS m/z(%): 422 (MH+, 100%), 249 (2%), 98 (16%).

[0424] The appropriate w-(6-acetylamino-1-indanyl)-alkanoic acids wereconverted to the corresponding acid chloride as described in Example 17,and reacted as described in Example 18 with6-Chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole to give thefollowing compounds:

[0425]6-Chloro-3-[1-[2-(6-acetylaminoindan-1-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indoleoxalate, 18c.

[0426] Mp 153-155° C., ¹H NMR (DMSO-d₆) δ1.60-1.90 (2H, m), 2.00 (3H,s), 2.10-2.35 (2H, m). 2.65-2.90 (4H, m), 3.05-3.30 (3H, m), 3.30-3.50(2H, m), 3.90 (2H, bs), 6.10 (1H, s), 7.05-7.15 (2H, m), 7.25 (2H, d),7.45 (1H, s). 7.60 (2H, m). 7.85 (1H, d), 9.90 (1H, bs), 11.50 (1H, bs).MS m/z (%/): 434 (MH+, 3 %), 188 (100%). 231 (14%), 174 (12%).

[0427] 6-Chloro-3-[1-[3-(6-acetylaminoindan-1-yl)propan-I-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole oxalate, 18d.

[0428] Mp 110-115° C., ¹H NMR (DMSO-d₆) δ1.35-1.50 (1H, m), 1.60-1.70(1H, m), 1.80 (3H, bs), 2.00 (3H, s), 2.20-2.39 (1H, m), 2.65-2.90 (4H,m), 3.05-3.20 (3H, m), 3.90 (2H, bs), 3.80 (2H, bs), 6.10 (1H, s),7.05-7.10 (2H, m), 7.25 (2H, d), 7.45 (1H, s), 7.55 (1H, d), 7.80 (1H,d), 9.80 (1H, bs). 11.50 (1H, bs). MS m/z (%): 448 (MH+, 5 %), 245(100%), 214 (35%), 246 (16%).

[0429]6-Chloro-3-[1-[4-(6-acetylaminoindan-1-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indoleoxalate, 18e.

[0430] Mp 125-128° C., ¹H NMR (DMSO-d₆) δ1.25-1.50 (31, m), 1.50-1.90(4H, m), 2.00 (3H, s), 2.10-2.30 (1H, m), 2.60-2.90 (4H, m), 2.90-3.15(3H, m), 3.40 (2H, bs), 3.80 (2H, bs), 6.10 (1H, s), 7.00-7.10 (2H, m),7.25 (1H, d), 7.45 (1H, s), 7.55 (1H, d), 7.80 (1H, d), 9.85 (1H, bs),11.50 (1H, bs). MS m/z (%): 462 (MH+, 4 %), 259 (100%), 186 (43%), 228(17%).

[0431] 2-(6-acetylaminoindan-1-yl)acetic acid,3-(6-acetylaminoindan-1-yl)propanoic acid and4-(6-acetylaminoindan-1-yl)butanoic acid were prepared from6-nitro-1-indanecarboxylic acid by classical chain elongations by usingKCN or diethyl malonate. The methodology is described for an analogousindane serie by R. Gruber et al. Tetrahedron 1974, 30, 3605-10. Alanewas used for the reduction of the intermediate carboxylic acids.

[0432]3-[1-(5-Acetylaminoindan-2-yl)methyl-1,2,3,6-tetrahydropyridine-4-yl]-6-chloro-1H-indole,oxalate, 18f.

[0433] Prepared from 17b. Mp 201-203° C. ¹H NMR (DMSO-d₆) δ2.00 (s, 3H),2.55-3.20 (m, 11H), 3.55 (broad s, 2H), 6.15 (broad s, 1H), 7.00-7.15(m, 2H), 7.25 (d, 1H), 7.45 (d, 1H), 7.50 (broad s, 2H), 7.85 (d, 1H),9.80 (s, 1H), 11.40 (broad s, 1H). MS m/z (%): 420 (MH+, 5%). 217 (12%),174 (100%).

[0434]3-[1-(5-Acetylaminoindan-2-yl)methylpiperidin-4-yl]-6-chloro-1H-indole,hemifumerate 18g.

[0435] Prepared from 17b. Mp 151-152° C. ¹H NMR (DMSO-d₆) δ1.65-2.05 (m,7H), 2.30 (t, 2H), 2.45-2.90 (m, 6H), 2.90-3.20 (m, 4H), 6.55 (s, 1H),6.95 (dd, 1H), 7.10 (d. 1H), 7.15 (d, 1H), 7.25 (dd. 1H), 7.40 (d, 1H),7.50 (s, 1H), 7.60 (d, 1H), 9.80 (s, 1H), 10.95 (broad s, 1H). MS m/z(%): 424. 422 (MH+, 19%, 54%), 249 (13%), 98 (100%).

EXAMPLE 19

[0436] 1-Acetyl-2,3-dihydro-3-12-(methanesulphonyl)ethyl]-1H-indole,19a.

[0437] (Intermediate)

[0438] To a solution of indole-3-acetic acid (100 g) in methanol (1l)was added ether saturated with HCl (200 ml), and the solution was leftat room temperature for 3 hours. The solution as evaporated in vacuo,and the residue was dissolved in THF 1.2 1) and added slowly withcooling to a stirred suspension of LiAlH₄ (28.6 g) in THF (1l). Afterstirring for 2 hours at room temperature, the mixture was cooled in anice bath, and water (57 ml), 15% NaOH (29 ml), and water (143 ml) wasadded. The mixture was filtered and evaporated in vacuo, and the residue(84.9 g) was dissolved in dioxane (1.5 l). Borane trimethylamine complex(200 g) was added, and and to the stirred mixture was added concentratedhydrochloric acid (150 ml) during 1 hour. The mixture was heated to 40°C. for 30 minutes and then to reflux for 2.5 hours. Then 6 Mhydrochloric acid (460 ml) was added and reflux was continued for 30minutes. The solution was concentrated in vacuo, and the residue waspoured on ice. The solution was washed with ether and was made basicwith concentrated NaOH and then extracted with ether. The organic phasewas dried over MgSO₄ and was evaporated in vacuo. The residue wasdissolved in CH₂Cl₂ (680 ml) and triethylamine (68 ml). Acetyl chloride(36 ml) was added at 5° C. during 1 hour. After further stirring for 1hour at room temperature, the mixture was washed with dilutehydrochloric acid, and NaHCO₃ solution. After drying over MgSO₄ andevaporation in vacuo, the residue was dissolved in methanol (500 ml),and 30% Na-methanolat (10 ml) was added. The mixture was stirred for 4hours at room temperature and was then evaporated in vacuo and wasdissolved in CH₂Cl₂ and was washed with saturated NaCl solution, driedover MgSO₄ and evaporation in vacuo. The residue (75.4 g) was dissolvedin CH₂Cl₂ (1 l) and triethylamine (100 ml). With cooling was added asolution of methanesulphonic chloride (27 ml) in CH₂Cl₂ (175 ml) at 10°C. After stirring for 30 minutes at 0° C. and 1 hour at roomtemperature, the mixture was evaporated in vacuo and was purified onsilica gel eluted with ethyl acetate to give the title product as an oil(74 g).

[0439] In a similar manner the following compounds were prepared:

[0440] 1-Formyl-2,3-dihydro-3-[2-(methanesulphonyl)ethyl]-1H-indole,19b.

[0441] Formylation was done with a mixture of formic acid and aceticacid anhydride. The compound was an oil.

[0442]1-Acetyl-5-bromo-2,3-dihydro-3-12-(methanesulphonyl)ethyl]-1H-indole19c. Bromination was done by treatment of 19a with bromine in a mixtureof acetic acid and dichloromethane. The compound was an oil.

[0443]1-tert-Butoxycarbonyl-2,3-dihydro-3-[2-(methanesulphonyl)ethyl]-1H-indole,19d.

[0444] tert-Butoxycarbonylation was done with di-tert-butyl dicarbonate.The compound was an oil.

[0445]1-tert-Butoxycarbonyl-2,3-dihydro-3-[4-(methanesulphonyl)butan-1-yl]-1H-indole,19e.

[0446] From 4-(1H-indol-3-yl)butyric acid.

[0447] 1-Acetyl-5-fluoro-2,3-dihydro-3-(2-bromoethyl)-1H-indole, 19f

[0448] 5-fluoro-indole (15.0 g, 135.2 mmol) was dissolved in dry Et₂O(450 ml) and cooled to 0° C. before a solution of oxalyl chloride in dryEt₂O (50 ml) was added over 15 min. The mixture was stirred 30 min at 0°C. and 3 hours at room temperature. The crystals were collected byfiltration and washed with Et₂O to give 19.5 g of solid which wasdissolved in EtOH (140 ml) and cooled to 0° C. before triethylamine (9.6g) was added drop-wise. The mixture was refluxed for 3 hours and stirredat room temperature for 24 hours. The crystals were collected byfiltration and washed with H₂O and Et₂O to give 18.0 g of solid which,after drying in a vacuum oven, was dissolved in dry THF (150 ml) andadded drop-wise to a cooled suspension (5-15° C.) of LiAlH₄ (16.1 g) indry THF (350 ml). The mixture was refluxed for 4 hours and cooled to 10°C. After drop-wise addition of H₂O (16 ml), aqueous (15%) NaOH (16 ml)and H₂O (80 ml), the solution was filtered and evaporated to almostdryness. The remanence was dissolved in EtOAc and dried with MgSO₄.Evaporation of the solvent gave the 2-(5-fluoroindol-3-yl)ethanol (15.2g) as an oil, which was treated as described in Example 19, startingwith the borane trimethylamine reduction followed by acylation, to givethe mesylate of the title compound which was refluxed for 2 hours inacetone (200 ml) with LiBr (8.0 g). The mixture was cooled, filtered,evaporated and purified by column chromatography using EtOAc:heptane=1:2 as the eluent to give the title compound (9.0 g).

[0449] 1-Acetyl-5-methyl-2,3-dihydro-3-(2-bromoethyl)-1H-indole, 19g

[0450] Prepared in a similar manner as 19f.

EXAMPLE 20

[0451]3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,20a.

[0452] A mixture of of6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.6 g), 19a (2.0g), K₂CO₃ (4.0 g), and methylisobutylketone (20 ml) was refluxed for 16hours. The mixture was filtered and evaporated in vacuo, and the residuewas purified on silica gel eluted with ethylacetate-methanol-triethylamine (90:5:5). Crystallization from ethanolgave the title product (0.3 g). Mp 172-4° C. ¹H NMR (DMSO-d₆) δ1.75-1.95(m, 1H). 2.05-2.20 (m, 1H), 2.25 (s, 3H), 2.50-2.65 (m. 4H). 2.75 (t.2H), 3.25 (broad s, 2H), 3.45-3.60 (m, 1H), 3.80 (dd, 1H), 4.20 (t, 1H),6.15 broad s, 1H), 7.00-7.15 (m, 3H), 7.25 (d, 1H), 7.45 (d, 2H), 7.80(d, 1H), 8.15 (s, 1H), 8.25 (d, 1H) MS m/z (%). 420 (MH+, 7%), 174(100%), 144 (55%).

[0453] In a similar manner the following compounds were prepared:

[0454]3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethylpiperidin-4-yl]-6-chloro-1H-indole,20b.

[0455] From 19a and 6-chloro-3-(piperidin-4-yl)-1H-indole (EP Patentpublication No 465398-A1). Mp 88-90° C. ¹H NMR (DMSO-d₆) δ1.70-1.90 (m,3H), 1.95-2.20 (m, 5H), 2.25 (s, 3H), 2.40-2.55 m, 2H), 2.80 (tt, 1H),3.00-3.10 (m, 2H), 3.40-3.55 (m, 1H), 3.75 (dd, 1H), 4.20 (t, 1H), 6.95(d, 1H), 7.05 (ddd, 1H), 7.25 (dt, 1H), 7.35 (d, 1H), 7.55 (d, 1H), 8.00(s, 1H), 8.25 (d, 1H). MS m/z (%): 422 (MH+, 100%), 249 (15%), 146(19%).

[0456]6-Chloro-3-[1-[2-(1-formyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole.20c.

[0457] From 19b and6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.

[0458] Mp 183-5° C. (from acetone). ¹H NMR (DMSO-d₆, the spectrum showshindered rotation which is eliminated by heating above 100° C.) δ1.60-1.80 (m, 1H), 1.95-2.10 (m, 1H), 2.35-2.55 (m, 4H), 2.70 (t, 2H),3.15 (s, 2H), 3.35-3.55 (m, 1H), 3.65 (dd, 0.76H), 3.90 (dd, 0.24H),4.10 (t, 0.76H), 4.30 (t, 0.24H), 6.15 (s, 1H), 6.95-7.15 (m, 2H), 7.25(t, 1H), 7.35 (d, 1H), 7.40-7.50 (m, 3H), 7.80 (d, 0.76H), 7.90 (d,0.24H), 8.50 (s, 0.24H), 9.05 (s, 0.76H), 11.20 (s, 1H). MS m/z (%): 406(MH+, 100%), 377 (5%), 244 (15%).

[0459] 6-Chloro-3-[1-[2-(1-formyl-2,3-dihydro-1H-indol-3-yl)ethylpiperidin-4-yl]-1H-indole, oxalate, 20d.

[0460] From 19b and 6-chloro-3-(piperidin-4-yl)-1H-indole. Mp 143-145°C. ¹H NMR (DMSO-d₆ the spectrum shows hindered) δ 1.75-2.30 (m, 6H),2.65-3.10 (m, 5H), 3.30-3.55 (m, 3H), 3.65 (dd, 0.8H), 3.90 (dd, 0.2H),4.10 (t, 0.8H), 4.25 (t, 0.2H), 6.95 (dd, 1H), 7.00-7.40 (m, 5H), 7.45(d, 0.8H), 7.60 (d, 1H), 7.95 (d, 0.2H), 8.50 (s, 0.2H), 9.05 (s, 0.8H),11.10 (s, 1H). MS m/z (%): 410, 408 (MH+, 9%, 25%), 146 (11%), 98(100%).

[0461]3-1-[2-(1-Acetyl-5-bromo-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,oxalate 20e.

[0462] From 19 c and6-chloro-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. Mp 157-159° C. ¹HNMR (DMSO-d₆) δ 1.80-2.00 (m. 1H), 2.10-2.40 (m, 1H), 2.20 (s, 3H), 2.70(broad s, 2H), 2.90-3.15 (m. 2H), 3.20 (broad s, 2H), 3.45-3.60 (m, 1H),3.65 (broad s, 2H), 3.85 (dd, 1H), 4.25 (t, 1H), 6.15 (broad s, 1H),7.10 (dd, 1H), 7.35 (dd. 1H), 7.45 (d, 1H), 7.55 (s, 2H), 7.85 (d. 11H),8.00 (d, 1H), 11.45 (broad s, 1H). MS m/z (%): 502, 500, 498 (MH+, 8%.27%, 22%). 297 (95%), 295 (100%).

[0463]3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-7-chloro-1H-indole,oxalate 20f.

[0464] From 19a and 7-chloro-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. Mp 171-173° C. ¹H NMR (DMSO-d₆) δ 1.90-2.00 (m, 1H), 2.20(s, 3H), 2.20-2.30 (m, 1H), 280 (broad s, 2H), 3.10-3.30 (m, 2H), 3.40(broad s, 2H), 3.50 (t, 1H), 3.80-3.95 (m, 3H), 4.25 (t, 1H), 6.15(broad s, 1H), 6.95-7.15 (m, 2H), 7.15-7.25 (m, 2I), 7.35 (d, 1H), 7.60(s, 1H), 7.80 (d, 1H), 8.05 (d. 1H), 11.65 (broad s, 1H). MS m/z (%):422, 420 (MH+, 3%, 7%), 174 (100%), 144 (43%).

[0465]3-[1-t2-(I-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6,7-dichloro-1H-indole,oxalate 20g.

[0466] From 19a and6,7-dichloro-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. Mp 115-117° C.¹H NMR (DMSO-d₆) δ 1.90-2.05 (m, 1H), 2.20 (s, 3H), 2.20-2.35 (m, 1H),2.80 (broad s, 2H), 3.10-3.30 (m, 2H), 3.40 (broad s, 2H), 3.50 (broads, 1H), 3.80-3.95 (m, 3H), 4.25 (t, 1H), 6.15 (broad s, 1H), 7.05 (t,1H), 7.20 (t, 1H), 7.25 (d, 1H), 7.35 (d, 1H), 7.65 (s, 1H), 7.80 (d,1H), 8.05 (d, 1H), 11.90 (broad s, 1H). MS m/z(%): 456, 454 (MH+, 4%,6%), 217 (36%). 174 (100%), 144 (36%).

[0467]3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-5,6-methylenedioxy-1H-indole,oxalate 20h.

[0468] From 19a and5,6-methylenedioxy-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. Mp 182-183° C. ¹H NMR (DMSO-d₆) δ 1.90-2.00 (m, 1H), 2.20 (s, 3H), 2.20-2.30 (m,1H), 2.75 (broad s, 2H), 3.10-3.30 (m, 2H), 3.40 (broad s, 2H), 3.50(broad s, 1H), 3.80-3.90 (m, 3H), 4.20 (t, 1H), 5.95 (s, 2H), 6.05(broad s, 1H), 6.95 (s, 1H), 7.05 (t, 1H), 7.20 (t, 1H), 7.25-7.40 (m,3H), 8.05 (d, 1H), 11.15 (broad s, 1H). MS m/z (%): 430 (MH+, 6%), 217(26%), 174 (100%), 144 (62%).

[0469]3-[1-[2-(1-tert-Butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,oxalate 20i.

[0470] From 19d and 6-chloro-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.Mp 132-135° C. ¹H NMR (DMSO-d₆) δ 1.55 (s, 9H), 1.90-2.00 (m, 1H),2.20-2.30 (m, 1H), 2.80 (broad s, 2H), 3.10-3.25 (m. 2H), 3.40 (broad s,3H), 3.65 (dd, 1H), 3.85 (broad s, 2H), 4.10 (t. 1H), 6.15 (broad s,1H), 6.95 (t, 1H), 7.10 (d. 1H), 7.20 (t, 1H), 7.30 (d, 1H), 7.50 (s,1H), 7.55 (s. 1H), 7.60-7.80 (broad s, 1H), 7.85 (d. 1H), 11.60 (broads, 1H). MS m/z (%): 478 (MH+, 10%). 219 (100%), 144 (27%).

[0471]5-[4-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-1H-indole,hydrochloride. 20j.

[0472] Prepared from 19a and 5-piperazinyl-1H-indole. Mp 241-243° C. ¹HNMR (DMSO-d₆) δ 1.95-2.15 (m 1H), 2.20 (s. 3H). 2.25-2.35 (m, 1H),3.15-3.50 (m. 6H). 3.55 (broad s. 1H), 3.70 (d. 4H), 3.90 (dd, 1H), 4.25(t, 1H), 6.40 (s, 1H), 6.95-7.10 (m, 2H), 7.20 (t, 1H ), 7.25-7.45 (m,4H), 8.05 (d, 1H), 11.10 (s, 1H). MS m/z(%): 389 (MH+, 71%), 159 (71%),118 (100%).

[0473]3-[1-[3-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)propyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,oxalate 20k.

[0474] From compound 22a. Mp 112-115° C. ¹H NMR (DMSO-d₆) δ 1.45-1.60(m, 1H), 1.70-1.90 (m, 3H), 2.20 (s, 3H), 2.80 (broad s, 2H), 3.15(broad s, 2H), 3.30-3.50 (m, 3H), 3.70-3.90 (m, 3H), 4.25 (t, 1H), 6.15(broad s, 1H), 7.00 (t, 1H), 7.10 (d, 1H), 7.20 (t, 1H), 7.30 (d, 1H),7.45 (s, 1H), 7.55 (s, 1H), 7.85 (d, 1H), 8.05 (d, 1H), 11.60 (broad s,1H). MS ml/z (%): 436, 434 (MH+, 2%, 5%), 231 (100%), 189 (36%), 158(70%).

[0475]3-[1-[2-(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,201.

[0476] Prepared from 19f and 6-chloro-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. Mp 183-185° C. ¹H NMR (DMSO-d₆) δ1.65-1.75 (m, 1H),2.00-2.10 (in, 1H), 2.15 (s, 3H), 2.40-2.55 (m, 4H), 2.60-2.75 (in, 2H),3.05-3.25 (dd, 2H), 3.45 (bs, 1H), 3.80-3.90 (m, 1H), 4.25 (t, 1H), 6.10(bs, 1H), 6.95 (t, 1H), 7.05 (d, 1H), 7.15 (d, 1H), 7.40 (s, 2H), 7.80(d, 1H), 8.05 (m, 1H), 11.20 (bs, 1H). MS m/z (%): 438 (MH+, 7 %), 162(100%), 192 (63%), 235 (58%).

[0477]3-[1-[2-(1-Acetyl-5-methyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,20m.

[0478] Prepared form 19g and 6-chloro-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. Mp 179-181° C. ¹H NMR (DMSO-d₆) δ1.60-1.70 (m, 1H),1.95-2.05 (m, 1H), 2.15 (s, 3H), 2.25 (s, 3H), 2.40-2.60 (m, 4H), 2.65(bs, 2H), 3.05-3.20 (dd, 2H), 3.40 (bs, 1H), 3.75-3.85 (m, 1H), 4.20 (t,1H), 6.10 (bs, 1H), 6.90 (d, 1H), 7.00 (d, 1H), 7.05 (s, 1H), 7.40 (s,2H), 7.80 (d, 1H), 7.90 (d, 1H), 11.25 (bs, 1H). MS m/z (%): 434 (MH+, 3%), 188 (100%), 158 (31%), 231 (21%).

EXAMPLE 21

[0479] 6-Chloro-3-[1-(indan-2-ylmethyl)piperidin-4-yl]-1H-indoleoxalate, 21a.

[0480] To a solution of 11a (0.51 g) in ethanol (40 ml) and acetic acid(10 ml) was added platinum oxide (0.12 g). The mixture was shaken for4.5 hours under 3 atm. hydrogen pressure. The mixture was filtered andevaporated in vacuo. The residue was dissolved in CH₂Cl₂ and the organicphase was shaken with dilute ammoniumhydroxide and then worked up in aconventional manner to give 0.46 g of crude product, from which thetitle product was crystallized as the oxalate salt from acetone. Yield0.36 g, mp 229-30° C. ¹H NMR (DMSO-d₆) δ1.85-2.10 (mi, 4H), 2.65-3.15(m, 10H), 3.50 (d, 2H), 7.00 (dd, 1H), 7.10-7.20 (m, 2H), 7.20-7.30 (m,3H), 7.40 (d, 1H), 7.65 (d, 1H), 11.05 (s, 1H). MS m/z (%): 365 (MH+,100%), 249 (17%), 131 (20%).

[0481] In a similar manner the following compounds were prepared:

[0482] 3-[1-(Indan-2-ylmethyl)piperidin-4-yl]-1H-indole 21b.

[0483] Prepared from 11b Mp 146-147° C. ¹H NMR (CDCl₃) δ 1.85 (q, 2H),2.05 (d, 2H), 2.20 (t, 2H), 2.45 (d, 2H), 2.65-2.90 (m, 4H), 3.00-3.20(m, 4H), 6.95 (s, 1H), 7.05-7.30 (m, 6H), 7.35 (d, 1H), 7.65 (d, 1H),7.95 (broad s, 1H). MS m/z (%): 331 (MH+, 11%), 131 (11%), 98 (100%).

[0484] 7-Chloro-3-[1-(indan-2-ylmethyl)piperidin-4-yl]-1H-indole,oxalate 21c.

[0485] Prepared from 11c. Mp 218-219° C. ¹H NMR (DMSO-d₆) δ 2.00-2.25(m, 4H), 2.70-2.85 (m, 2H), 2.85-3.35 (m, 8H), 3.55 (d, 2H), 7.00 (t,1H), 7.10-7.30 (m, 6H), 7.65 (d, 1H), 11.30 (broad s, 1H). MS m/z (%):367, 365 (MH+, 9%, 25%), 131 (14%), 98 (100%).

[0486] 6,7-Dichloro-3-[1-(indan-2-ylmethyl)piperidin-4-yl]-1H-indole,21d. Prepared from 11d. Mp 141-142° C. ¹H NMR (CDCl₃) δ 1.75-1.90 (m,2H), 2.00 (d, 2H), 2.15 (t, 2H), 2.45 (d, 2H), 2.65-2.85 (m, 4H),3.00-3.15 (m, 4H), 7.00 (s, 1H), 7.10-7.25 (m, 5H), 7.45 (d, 1H), 8.20(broad s, 1H). MS m/z (%): 401, 399 (MH+, 17%, 26%), 131 (19%), 98(100%).

[0487]3-[1-(Indan-2-ylmethyl)piperidin-4-yl-5,6methylenedioxy-1H-indole, 21e.

[0488] Prepared from 11e. Mp 187-188° C. ¹H NMR (DMSO-d₆) δ 1.55-1.70(m, 2H), 1.90 (d, 2H), 2.05 (t, 2H), 2.30 (d, 2H), 2.60-2.75 (m, 4H),2.85-3.05 (m, 4H), 5.90 (s, 2H), 6.85 (s, 1H), 6.90 (s, 1H), 7.00 (s,1H), 7.05-7.15 (m, 2H), 7.15-7.25 (m, 2H), 10.55 (broad s, 1H). MS m/z(%): 375 (MH+, 10%), 131 (9%), 98 (100%).

[0489] 6-Chloro-3-[1-[2-(indan-2-yl)ethyl]piperidin-4-yl]-1H-indole, 21f. Prepared from 11g. Mp 155-156° C. ¹H NMR (DMSO-d₆) δ 1.60-1.75 (m,4H), 1.90 (d, 2H), 2.05 (t, 2H), 2.35-2.45 (m, 3H), 2.45-2.60 (m, 2H),2.70 (t, 1H), 2.90-3.05 (m, 4H), 6.95 (d, 1H), 7.05-7.20 (m, 5H), 7.35(s, 1H), 7.55 (d, 1H), 10.90 (broad s, 1H). MS m/z (%): 381, 379 (MH+,33%, 89%), 228 (45%), 145 (44%), 98 (100%).

[0490]6-Chloro-3-[1-[3-(indan-2-yl)propan-1-yl]piperidin-4-yl]-1H-indole, 21g

[0491] Prepared from 11h. Mp 134-135° C. ¹H NMR (CDCl₃) δ 1.45-1.60 (m,2H), 1.60-1.75 (m, 2H), 1.75-1.90 (m, 2H), 2.05 (d. 2H), 2.10 (t, 2H),2.35-2.55 (m, 3H), 2.55-2.65 (m, 2H), 2.80 (t, 1H), 2.95-3.15 (m, 4H),6.95 (s, 1H), 7.00-7.25 (m, 5H), 7.30 (s, 1H), 7.55 (d, 1H), 8.10 (broads, 1H). MS m/z (%): 395, 393 (MH+, 8%, 21%), 242 (53%), 117 (52%), 98(100%).

[0492]6-Chloro-3-[1-[4-(indan-2-yl)butan-1-yl]piperidin-4-yl]-1H-indole, 21h.

[0493] Prepared from 11i Mp 139-140° C. ¹H NMR (CDCl₃) δ 1.30-1.70 (m,6H), 1.70-1.95 (m, 2H), 1.95-2.20 (m, 4H1), 2.35-2.65 (m, 5H), 2.70-2.90(m. 1H), 2.95-3.15 (m, 4H), 6.95 (d, 1H), 7.00-7.25 (m, 5H), 7.35 (d,1H), 7.55 (d, 1H), 8.05 (broad s, 1H). MS m/z (%): 409, 407 (MH+, 32%,90%), 256 (96%), 98 (100%).

EXAMPLE 22

[0494] 1-Acetyl-3-(3-bromopropan-1-yl)-2,3-dihydro-]H-indole, 22a

[0495] (Intermediate)

[0496] A mixture of 3-(1H-indol-3-yl)propionic acid (10 g), methanol(200 ml), and a saturated solution of HCl in ether (75 ml) was stirredat room temperature for 4 days. The solvents were removed in vacuo, andthe residue was worked up in a conventional manner by the use of diluteammonium hydroxide and ethyl acetate to yield an oil (10.6 g). The oilwas dissolved in acetic acid (200 ml), and NaCNBH₄ (12 g) was added inparts of I g. The mixture was stirred at room temperature for 48 h, andthen poured into ice-cooled water. The pH of the solution was adjustedto 8 with ammonium hydroxide (25%), and the aqueous phase was extractedwith ether. The combined organic phases were extracted with I M HClsolution. The pH of the aqueous phase was adjusted to 8 with ammoniumhydroxide and extracted with ethyl acetate. The combined organicextracts were washed with brine, dried (MgSO₄), and the solvent wasremoved in vacuo. The residue was purified on silica gel eluted withethyl acetate-heptane (1:1) to give an oil (6.1 g). The residue wasdissolved in THF (50 ml) and added to a suspension of LiAlH₄ (2.0 g) inTHF (100 ml) at about 30° C. The mixture was stirred at room temperaturefor 15 min and then cooled to 5° C. By drop-wise addition, water (4.0ml), 15% NaOH solution (2.0 ml), and water (10 ml) was added. Themixture was dried (MgSO₄) and concentrated in vacuo. The oil wasdissolved in THF (200 ml), added triethylamine (11 ml) and cooled to-20° C. To this mixture, a solution of acetyl chloride (2.1 ml) in THF(50 ml) was added, and the mixture was allowed to warm to 5° C. To thismixture, a solution of methanesulfonyl chloride (2.1 ml) in THF (50 ml)was added. Ether (200 ml) was added and the mixture was filtered. Themother liquid was concentrated in vacuo and subjected to purification onsilica gel eluted with ethyl acetate-heptane (4:1) to give a crystallinecompound (7.3 g). The compound was dissolved in acetone (500 ml), addedlithium bromide (10.3 g), and the mixture was boiled under reflux for 1h. The mixture was cooled, filtered and evaporated in vacuo to drynessto give the title compound.

[0497] The following compound was made in a similar manner

[0498] 1-Acetyl-2,3-dihydro-3-(2-iodoethyl)-1H-indole, 22b.

[0499] From 19a and lithium iodide

[0500] 2-Iodomethylindane, 22c.

[0501] From 2-indanemethanol methanesulfonate prepared from 9a asdescribed in Example and 3.

EXAMPLE 23

[0502] 7-Methoxy-1-indanecarboxylic acid, 23a

[0503] (Intermediate)

[0504] A mixture of 7-methoxy-1-indanone (25 g), prepared according toJ. Am. Chem. Soc. 1948, 70, 1386, ZnI₂ (0.5 g) in toluene (300 ml) wasadded trimethylsilyl cyanide (25 ml and further 15 ml after 3 h), andthe reaction mixture was stirred at 60° C. for 5 h. Water was added, andthe mixture stirred at room temperature for 1 h. The phases wereseparated, and the organic phase was dried (MgSO₄) and evaporated todryness in vacuo. The residue was purified on silica gel eluted withdichloromethane (25 g). The residue was dissolved in acetic acid (100ml) and 6 M HCl solution (100 ml), and the mixture was heated at 100° C.for 7 h. Acetic acid was removed in vacuo, and the aqueous phase wasextracted with ether. The combined organic phases were dried (MgSO₄),evaporated to dryness in vacuo and purified on silica gel eluted withdichloromethane (5 g). The residue was dissolved in ethanol (200 ml),the solution was added palladium on carbon (5%) (2 g), and the mixturewas shaken for 3 h under 3 atm. hydrogen pressure. The mixture wasfiltered and evaporated in vacuo (5 g). The residue was dissolved inacetic acid (10 ml), concentrated sulfuric acid (5 ml), and water (5ml), and the mixture was heated at 110° C. for 3 h. The mixture wascooled and extracted with ethyl acetate. The organic phases were washedwith water, added ether and extracted with 2 M NaOH solution. The pH ofthe aqueous phase was adjusted to 1 with hydrochloric acid and extractedwith ether. The combined organic phase was dried (MgSO₄) and evaporatedto dryness in vacuo to give the title compound (2 g).

[0505] The following compound was made in a similar manner:

[0506]6-Methoxy-1-indanecarboxylic acid, 23b.

[0507] From 6-methoxy-1-indanone.

EXAMPLE 24

[0508]2-(2-Iodoethyl)indane, 24a

[0509] (Intermediate)

[0510] A mixture of 2-(indan-2-yl)ethanol (19.3 g), imidazole (12.1 g),triphenylphosphine (34.3 g), and toluene (250 ml) was heated to 90° C.To this mixture, iodide (33.2 g) was added, and the resulting mixturewas stirred at 90° C. for 20 min. The mixture was allowed to cool toroom temperature, filtered, and concentrated in vacuo. The residue waspurified on silica gel eluted with ethyl acetate-heptane (1:4) to givean oil (28.4 g, 87%).

EXAMPLE 25

[0511] 4-[4-[2-(Indan-2-yl)ethyl]piperazin-1-yl]-1H-indole, 25a.

[0512] A mixture of 4-(piperazin-1-yl)-1H-indole (1.5 g),2-(2-iodoethyl)indane (2.0 g), K₂CO₃, methyl isobutyl ketone (150 ml),and N-methylpyrrolidone (10 ml) was boiled under reflux for 3 h. Themixture was allowed to cool to room temperature, filtered, andconcentrated in vacuo. The residue was purified on silica gel elutedwith ethyl acetate-heptane (1:2) to give a crystalline compound, whichwas recrystallized (ethyl acetate) to give the title compound (1.2 g,47%). Mp 146-147° C. ¹H NMR (CDCl₃) δ 1.70-1.85 (m, 2H), 2.40-2.70 (in5H), 2.75 (broad s, 4H), 3.00-3.15 (m, 2H), 3.30 (broad s, 4H), 6.55 (s,1H), 6.60 (d, 1H), 7.00-7.30 (m, 7H), 8.20 (broad s, 1H). MS m/z (%):346 (MH+, 34%), 159 (88%), 145 (100%).

[0513] The following compound was made in a similar manner:

[0514] 5-[4-[2-(Indan-2-yl)ethyl]piperazin-1-yl]-1H-indole,hydrochloride 25b.

[0515] Prepared 2.40-2.55 from 24a and 5-(piperazin-1-yl)-1H-indole. Mp251-253° C. ¹H NMR (DMSO-d₆) δ 1.90-2.05 (m, 2H),(m, 1H), 2.55-2.70 (m,2H), 3.00-3.15 (m, 2H), 3.25 (broad s, 2H), 3.50 (broad s, 2H), 3.75(broad s, 6H), 6.45 (s, 1H), 7.05-7.30 (m, 5H), 7.40 (s, 1H), 7.45 (d,1H), 7.55 (broad s, 1H), 11.30 (broad s, 1H). MS m/z (%): 346 (MH+,44%), 159 (87%), 145 (100%)

EXAMPLE 26

[0516] 5-Chloro-1-(pyridin-4-yl)-1H-indole , 26a.

[0517] (Intermediate)

[0518] A mixture of 5-chloro-1H-indole (20 g), 4-bromopyridine, HCl (45g), K₂CO₃ (55 g), CuBr (5 g), and Cu (2 g) was heated at 150° C. for 24h. The reaction mixture was cooled, poured into water (700 ml), andcrude product was collected by filtration. The crude product wasdissolved in ethyl acetate (1000 ml), and the organic phase was washedwith dilute ammonium hydroxide and saturated NaCl solution. The organicphase was dried (MgSO₄), and concentrated in vacuo (150 ml). Crystalline5-chloro-1-(pyrid-4-yl)-1-indole was collected by filtration (180 g60%). the following compound was made in a similar manner.

[0519] 1-(Pyridin-4-yl)-1H-indole, 26b.

EXAMPLE 27

[0520] 2-(Pyridin-4-yl)-1H-indole, 27a.

[0521] (Intermediate)

[0522] A mixture of isonicotic acid (7.1 g) and thionyl chloride (150ml) was boiled under reflux for 2 h and evaporated to dryness in vacuo.The residue was dissolved in DMF (100 ml) and added to a suspension of2-aminobenzyltriphenylphosphonium bromide (L. Capuano et al, Chem. Ber.1986. 119, 2069-2074) in dichloromethane. The resulting clear solutionwas stirred at room temperature for 2 h and concentrated in vacuo. Therude product was recrystallized (ethanol) to give 21.3 g of crystals.Compound corresponding to 1.0 g was suspended in toluene (25 ml), andthe mixture was heated to reflux temperature. Potassium tert-butoxide(0.44 g) was added at once, and the reaction mixture was boiled underreflux for 15 min, filtered hot, and concentrated in vacuo. Purificationon silica gel eluted with ethyl acetate-heptane-TEA (80.20:5) gave thetitle compound.

EXAMPLE 28

[0523]5-Chloro-1-[1-[2-(indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole28a.

[0524] A mixture of 5-chloro-1-(pyridin-4-yl)-1H-indole 26a (4.0 g),2-(2-iodoethyl)indane 24a (4.8 g). and methyl isobutyl ketone (100 ml)was boiled under reflux for 20 h. The mixture was cooled, and acrystalline compound collected by filtration (6.5 g). Compoundcorresponding to 5.5 g was suspended in methanol (100 ml), and NaBH₄(1.5 g) was added in parts of 0.5 g. The resulting mixture was stirredat room temperature for 1 h, and the solvent was removed in vacuo.Conventional work up with ethyl acetate and water followed bypurification on silica gel eluted with ethyl acetate-heptane (1: 1) gavethe crude product, which was crystallized (ethyl acetate) to give thetitle compound (1.1 g, 27%).

[0525] Mp 93-94° C. ¹H NMR (CDCl₃) δ 1.75-1.90 (m, 2H). 2.45-2.55 (m,1H), 2.55-2.70 (m, 6H), 2.75-2.90 (m, 2H), 3.05-3.15 (m, 2H), 3.25 (d.2H), 5.90 (broad s, 1H), 6.45 (s, 1H), 7.05-7.25 (m, 6H), 7.45 (d, 1H),7.60 (s. 1H). MS m/z (%): 377 (+, 6%), 143 (100%), 128 (50%).

[0526] The following compound was made in a similar manner:

[0527]1-[1-[2-(Indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,oxalate 28b.

[0528] Prepared from 24a and 26b. Mp 176-178° C. ¹H NMR (DMSO-d₆) δ1.85-1.95 (m, 2H), 2.40-2.55 (m, 1H), 2.55-2.70 (m, 2H), 2.85 (broad s,2H), 3.00-3.10 (m, 2H), 3.15 (t, 2H), 3.40 (broad s, 2H), 3.85 (broad s,2H), 5.95 (broad s, 1H), 6.60 (d, 1H), 7.05-7.25 (m, 6H), 7.55 (d, 1H),7.60-7.70 (m, 2H). MS m/z (%): 343 (MH+), 143 (100%), 128 (80%).

[0529]2-[1-[2-(Indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,28c.

[0530] Prepared from 27a and 24a. Mp 175-176° C. ¹H NMR (CDCl₃) δ1.75-1.85 (m, 2H), 2.45-2.55 (m, 1H), 2.55-2.60 (m, 2H), 2.60-2.70 (m,4H), 2.70-2.80 (m, 2H), 3.05-3.15 (m, 2H), 3.25 (broad s, 2H), 6.05(broad s, 1H), 6.45 (s, 1H), 7.05 (t, 1H), 7.10-7.25 (m, 5H), 7.35 (d,1H), 7.55 (d, 1H), 8.10 (broad s, 1H). MS m/z (%): 343 (MH+, 8%), 174(32%), 143 (100%).

[0531]2-[1-(Indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole, 28d.From 22c and 27a.

[0532]¹NMR (CDCl₃) δ 2.50-2.55 (m, 2H), 2.65 (broad s, 2H), 2.70-2.85(m, 5H), 3.00-3.15 (m, 2H), 3.25 (d, 2H), 6.05 (broad s, 1H), 6.45 (s,1H), 7.05 (t, 1H), 7.10-7.25 (m, 5H), 7.30 (d, 1H), 7.55 (d, 1H), 8.10(broad s, 1H). MS m/z (%): 329 (MH+, 5 %), 160 (4%), 131 (4%), 91 (6%),44 (100%).

[0533]2-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole28e. From 22b and 27a.

[0534]¹H NMR (DMSO-d₆) δ1.65-1.80 (m, 1H), 1.95-2.10 (m, 1H), 2.15 (s,3H), 2.45-2.60 (m, 4H), 2.65 (broad s, 2H), 3.10-3.20 (m, 2H), 3.40-3.50(m, 1H), 3.75-3.85 (m, 1H), 4.20 (t, 1H), 6.30 (s, 1H), 6.40 (s, 1H),6.90 (t, 1H), 6.95-7.10 (m, 2H), 7.15 (t, 1H), 7.25-7.35 (m, 2H), 7.45(d, 1H), 8.05 (d, 1H), 11.05 (broad s, 1H). MS m/z (%): 386 (MH+, 13%),217 (20%), 174 (10%), 144 (87%), 132 (45%), 44 (100%).

EXAMPLE 29

[0535] 5-Chloro-1-1-[2-(indan-2-yl)ethyl]piperidin-4-yl]-1H-indole, 29a.

[0536] A mixture of5-Chloro-1-[1-[2-(indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole.28a. (1.9 g), acetic acid (50 ml), and platinum oxide (0.1 g) was shakenfor 3 h under 3 atm. hydrogen pressure. The mixture was filtered andevaporated in vacuo. The residue was dissolved in ethyl acetate and theorganic phase was shaken with dilute ammonium hydroxide and then workedup in a conventional manner. Further purification was done on silica geleluted with ethyl acetate-heptane (1 :1) to give 2.0 g of crude product.The crude product was crystallized (ethyl acetate), and the titlecompound was collected by filtration (1.1 g, 58%)

[0537] Mp 108-109° C. ¹H NMR (CDCl₃) δ 1.70-1.80 (m, 211), 2.00-2 10 (m,4H ), 2.10-2.25 (m, 2H), 2.40-2.55 (m, 3H), 2.55-2.70 (m, 2H), 3.00-3.20(m, 4H), 4.10-4.25 (m, 1H), 6.45 (d, 1H), 7.05-7.35 (m, 7H), 7.60 (s,1H). MS m/z (%): 379 (MH+, 3%), 228 (13%), 145 (29%), 143 (28%), 98(100%).

[0538] The following compound was made in a similar manner:

[0539] 1-[1-[2-(Indan-2-yl)ethyl]piperidin-4-yl]-1H-indole, 29b.Prepared from 28b.

[0540] Mp 80-81° C. ¹H NMR (CDCl₃) δ 1.70-1.85 (m, 2H), 2.00-2.25 (m,6H), 2.40-2.55 (m, 3H), 2.55-2.70 (m, 2H), 3.00-3.20 (m, 4H), 4.15-4.30(m, 1H), 6.50 (d, 1H), 7.05-7.30 (m, 7H), 7.40 (d, 1H), 7.65 (d, 1H). MSm/z (%): 345 (MH+, 4%), 228 (9%), 145 (30%), 143 (34%), 98 (100%).

EXAMPLE 30

[0541]6-Chloro-3-[1-[2-(2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,oxalate 30a.

[0542] A mixture of3-[1-[2-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,oxalate 20i as the free base (4.0 g), dichloromethane (50 ml), and THF(25 ml) was cooled in an ice bath, and the mixture was addedtrifluoroacetic acid (40 ml). The reaction mixture was stirred at roomtemperature for 16 h and poured into an ice-cold solution of diluteammonium hydroxide. Conventional work up with ethyl acetate gave thecrude product. Crude product corresponding to 1.4 g was converted to theoxalate salt, which was recrystallized (methanol-ether-heptane) to givethe title compound (0.5 g).

[0543] Mp 109-111° C. ¹H NMR (DMSO-d₆) δ 1.80-2.00 (m, 1H), 2.10-2.30(m, 1H), 2.80 (broad s, 2H), 3.05-3.35 (m, 4H), 3.35-3.65 (m, 3H), 3.90(broad s, 2H), 6.15 (broad s, 1H), 6.45-6.65 (m, 2H), 6.95 (t, 1H),7.00-7.15 (m, 2H), 7.45 (d, 1H), 7.60 (d, 1H), 7.85 (d, 1H), 11.55 (d,1H). MS m/z (%): 378 (MH+, 4%), 169 (19%), 168 (38%), 144 (100%).

[0544] The following compound was made in a similar manner:

[0545]6-Chloro-3-11-[4-(2.3-dihydro-1H-indol-3-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole30b.

[0546] From 19e.

EXAMPLE 31

[0547]6-Chloro-3-1-[2-(2,3-dihydro-1-methylaminocarbonyl-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indoleoxalate, 31a

[0548] To a solution of6-chloro-3-[1-[2-(2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,oxalate 30a, as the free base, (3.6 g) in dichloromethane (100 ml) wasadded methylisocyanate (1.4 g) in dichloromethane (20 ml). The mixturewas stirred at room temperature for 16 h, and the solvent was removed invacuo. The residue was purified on silica gel eluted with ethylacetate-ethanol-triethylamine (90:10:5) to give the crude product, whichwas recrystallized (methanol-ethyl acetate-ether) to give the titlecompound (1.8 g). ¹H NMR (DMSO-d₆) δ 1.60-1.70 (m, 1H), 1.95-2.05 (m,1H), 2.40-2.60 (m, 4H), 2.60-2.75 (m, 5H), 3.15 (q, 2H), 3.35-3.50 (m,1H), 3.55-3.65 (m, 1H), 4.00 (t, 1H), 6.10 (broad s, 1H), 6.55 (d, 1H),6.85 (t, 1H), 7.05 (d, 1H), 7.10 (t, 1H), 7.20 (d, 1H), 7.45 (s, 2H),7.80 (d, 1H), 7.85 (d, 1H), 11.25 (broad s, 1H). MS m/z (%): 437, 435(MH+, 2%, 6%), 201 (54%), 189 (100%), 144 (64%).

EXAMPLE 32

[0549] (±)-Methyl(1-tert-Butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)acetate 32a.

[0550] (Intermediate)

[0551] A mixture of (1H-indol-3-yl)acetic acid (62 g), methanol (800ml), and a saturated solution of HCl in ether (200 ml) was stirred atroom temperature for 4 days. The solvents were removed in vacuo, and theresidue worked up in a conventional manner by the use of dilute ammoniumhydroxide and ethyl acetate to yield an oil (64 g). The oil wasdissolved in acetic acid (600 ml), and NaCNBH₄ (27.6 g) was added inparts of I g. The mixture was stirred at room temperature for 48 h, andthen poured into ice-cooled water. The pH of the solution was adjustedto 8 with ammonium hydroxide (25%), and the aqueous phase was extractedwith ethyl acetate (3×1 L). The combined organic phases were washed withbrine, dried (MgSO₄), and the solvent was removed in vacuo (73 g). Theresidue was then dissolved in THF (500 ml), and to this mixture, asolution of di-tert-butyl dicarbonate (89 g) in THF (500 ml) was added.The reaction mixture was stirred at room temperature for 24 h, and thesolvent was removed in vacuo. The crude product was purified on silicagel eluted with ethyl acetate-heptane (1:4) to give the title compoundas an oil (92 g).

EXAMPLE 33

[0552] (+)-(1-tert-Butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)acetic acid33a.

[0553] (intermediate)

[0554] Candida Antarctica Lipase (CAL, SP-435, Novo Nordisk,Denmark)(2.5 g) was suspended in

[0555] (±)-methyl(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)acetate 32a (50 g), andthis mixture was further suspended in a 0.1 M phosphate buffer (pH=7.0)(3 L) under vigorous stirring. The reaction mixture was maintained at25° C., and the pH was maintained at 7 by the addition of 0.5 M NaOHsolution. The reaction could be monitored by the amount of added NaOH,and it was stopped after the addition of about 0.45 equivalent of base(about 120 h). The enzym was filtered of and washed with ether (1 l ).The pH of the water phase was adjusted to 8. The aqueous phase wasextracted with ether (2×1 l). The combined organic extracts were dried(MgSO₄) and evaporated to dryness in vacuo to give the starting esterenriched in a single enantiomer. The aqueous phase was cooled with ice,and the pH adjusted to 1.5 by the addition of conc. HCl. The aqueousphase was extracted with ether (3×1 l). The combined organic extractswere dried (MgSO₄) and the solvent was removed in vacuo to give thetitle compound in an enantiomeric excess of about 80-85%.Recrystallization from diisopropyl ether gave the title compound in anenantiomeric excess of 96.5%. [α]_(D)+12.8° (c=0.45, methanol). Mp137-138° C.

[0556] (−)-(1-tert-Butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)acetic acid33b. The enriched ester from the synthesis of 33a was treated once againas described for the racemate 32a, and the reaction mixture was workedup in a similar manner as 33a. Ester enriched in a single enantiomercorresponding to 33.7 g was dissolved in ethanol (500 ml) and treatedwith 1 M NaOH solution (500 ml). The mixture was stirred at roomtemperature for 30 min, and the ethanol was removed in vacuo. Theaqueous phase was washed with ether, cooled by the addition of ice, andthe pH was adjusted to 1. The aqueous phase was extracted with ether(3×400 ml), and the combined organic extracts were washed with brine,dried (MgSO₄), and the solvent was removed in vacuo (31 g, enantiomericexcess of 94.6%). The residue was crystallized from diisopropyl ether(50 ml) to give the title compound in an enantiomeric excess of 97.7%(26 g). [α]_(D)=−12.6° (c=0.47, methanol). Mp 136-137° C. Chiral HPLCanalysis was performed on an apparate equipped with UV detector (set at230 nm). The analysis was performed on a on a Ultron ES OVM 150×4.6 mm,flow 1.0 ml/min, eluent 25 mM phosphate buffer(pH=4.6)/methanol/isopropanol/THF 90/5/5/0.5, T= 30° C. Enantiomericpurities expressed as enantiomeric excess (ee) were calculated from peakareas.

EXAMPLE 34

[0557](+)-(3-1-12-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,34a.

[0558] A mixture of(+)-(1-tert-butoxycarbonyl-2.3-dihydro-1H-indol-3-yl)acetic acid 33a(5.0 g). methanol (200 ml), and a saturated solution of HCl in ether (50ml) was stirred at room temperature for 16 h. The solvent was removed invacuo, and the residue was dissolved in ice-cooled water. The aqueousphase was washed with ether, and the pH was adjusted to 8 with asaturated solution of NaHCO₃. The aqueous phase was extracted with ethylacetate (3×150 ml), and the combined organic extracts were washed withbrine, dried (MgSO₄), and evaporated to dryness in vacuo (3.4 g). Theresidue was dissolved in THF (50 ml) and added to a suspension of LiAlH4(1.6 g) in THF (150 ml) at about 30° C. The mixture was stirred at roomtemperature for 30 min and then cooled to 5° C. By drop-wise addition,water (3.2 ml), 15% NaOH solution (1.6 ml), and water (8 ml) was added.The mixture was dried (MgSO₄) and concentrated in vacuo. The residue waspurified on silica gel eluted with ethyl acetate-ethanol (200:5) to givean oil (2.6 g). The oil was dissolved in dichloromethane (80 ml), addedtriethylamine (2.7 ml) and cooled to -30° C. To this mixture, a solutionof acetyl chloride (1.1 ml) in dichloromethane (10 ml) was added, andthe mixture was allowed to warm to 5° C. Triethylamine (2.7 ml) wasadded, and to this mixture, a solution of methanesulfonyl chloride (1.3ml) in dichloromethane (10 ml) was added. The reaction mixture waspurified on silica gel eluted with ethyl acetate-heptane (4:1) to givean oil (4.5 g). The oil was dissolved in methyl isobutyl ketone (100 ml)and added to a mixture of of6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (5.5 g), K₂CO₃(4.4 g), methyl isobutyl ketone (100 ml), and N-methylpyrrolidone (10ml) under reflux. The mixture was boiled under reflux for 6 h andevaporated to dryness in vacuo. The residue was purified on silica geleluted with ethyl acetate-ethanol (10:1) to give the crude product,which was recrystallized (ethyl acetate) to give the title compound (2.9g) in an enantiomeric excess of 97.4%. [α]_(D)=+35.9° (c=0.25,methanol). Mp 169-170° C. ¹H NMR (DMSO-d₆) δ 1.65-1.80 (m, 1H),2.00-2.10 (m, 1H), 2.15 (s, 3H), 2.45-2.60 (m, 4H), 2.65 (broad s, 2H),3.05-3.20 (m, 2H), 3.40-3.50 (m, 1H), 3.80 (dd, 1H), 4.25 (t, 1H), 6.10(broad s, 1H), 6.95-7.05 (m, 2H), 7.15 (t, 1H), 7.30 (d, 1H), 7.40-7.45(m, 2H), 7.80 (d, 1H), 8.05 (d, 1H),,11.20 (broad s, 1H). MS m/z (%):422, 420 (MH+, 3%, 8%), 217 (30%), 174 (100%), 144 (41%).

[0559] The following compound was made in a similar manner: From 33b.

[0560] (−)-(3-[12-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,34b.

[0561] Enantiomeric excess of 98.4%. [α]_(D)=−34.9 (c=0.27, methanol).Mp 168-169° C. Chiral HPLC analysis was performed on an apparatusequipped with UV detector (set at 230 nm). The analysis was performed ona Chiral AGP 100×4 mm, flow 0.8 ml/min, eluent 25 mM phosphate buffer(pH=6.0)/methanol/isopropanol/THF/90/5/5/1, T=25° C. Enantiomericpurities expressed as enantiomeric excess (ee) were calculated from peakareas.

EXAMPLE 35

[0562]3-[1-[4-(1-Acetyl-2,3-dihydro-1H-indol-3-yl]butan-1-yl-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,35

[0563] A mixture of6-chloro-3-[1-[4-(2,3-dihydro-1H-indol-3-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole30b (4.9 g), triethylamine (3.7 g), and THF (200 ml) was cooled (5° C.),and the mixture was added a solution of acetyl chloride (1.0 g) in THF(50 ml). The reaction mixture was allowed to warm to room temperature,filtered and concentrated in vacuo. The residue was purified on silicagel eluted with ethyl acetate-ethanol-triethylamine (90:10:5) to givethe crude product, which was recrystallized (methanol-ethyl acetate) togive the title compound (2.7 g). ¹H NMR (DMSO-d₆) δ 1.30-1.45 (m, 2H),1.45-1.60 (m, 3H), 1.75-1.85 (m, 1H), 2.15 (s, 3H), 2.40 (t, 2H),2.45-2.55 (m, 2H), 2.55-2.65 (m, 2H), 3.10 (broad s, 2H), 3.40 (broad s,1H), 3.70-3.80 (m, 1H), 4.20 (t, 1H), 6.10 (broad s, 1H), 6.95 (t, 1H),7.05 (d, 1H), 7.15 (t, 1H), 7.25 (d, 1H), 7.40 (s, 2H), 7.80 (d, 1H),8.05 (d, 1H), 11.20 (broad s, 1H). MS m/z (%) 448 (MH+, 3%), 245 (17%),172 (100%).

EXAMPLE 36

[0564] 2,3-Dimethyl-1-(2-propyl)oxybenzene, 36a.

[0565] (Intermediate)

[0566] To a stirred solution/suspension of 2,3-dimethylphenol (10 g) andpotassium carbonate (6.8 g) in acetone (150 ml) at reflux was added2-bromopropane (46 ml) drop-wise over 30 min. The solution was heated atreflux for 4 days. After cooling, the solvent was evaporated and theresidue was dissolved in ether and water. The ether phase was separatedand was worked up according to the general procedure. Columnchromatography on silica gel (eluent :-ethyl acetate/heptane 1:19)afforded pure 2,3-dimethyl-1-(2-propyl)oxybenzene (13.2 g) as a mobile,slightly brown oil which was used without further purification.

EXAMPLE 37

[0567] 2,3-Di(bromomethyl)-1-(2-propyl)oxybenzene, 37a.

[0568] (Intermediate)

[0569] To a stirred solution of 2,3-dimethyl-1-(2-propyl)oxybenzene (10g) in carbon tetrachloride (150 ml) was added N-bromosuccinimide (22 g)and dibenzoyl peroxide (370 mg) and the mixture was heated at reflux for1.5 h. The solution was cooled to room temperature and was filtered. Theresidue was washed with further carbon tetrachloride (100 ml) and thecombined filtrates were evaporated to give2,3-di(bromomethyl)-1-(2-propyl)oxybenzene (21.0 g) as a yellow/orangeoil which was used without further purification.

[0570] 1,2-Dimethoxy-4,5-bis(chloromethyl)benzene, 37b

[0571] A stirred solution/suspension of veratrole (20 g), zinc chloride(3.2 g) and sodium chloride (420 mg) in ether (400 ml) was cooledto >20° C. using an ice-water bath, and HCl gas was bubbled through themixture for 10 minutes. The bubbling was continued, and formaldehydesolution (26 ml, 123 M in water) was added dropwise over 20 minutes.Stirring/bubbling was continued for a further 4 hours, after which therewas no further rise in temperature. During this time the temperature washeld between 20-30° C. by the addition of ice to the cooling bath. Thebubbling of HCl was then stopped, the flask was stoppered, and themixture was stirred overnight. The solution was evaporated, and thentaken up in ethyl acetate and water. The organic extractes were washedsuccessively with sodium hydrogen carbonate solution, brine, dried overmagnesium sulfate, and evaporated to yield a white/yellow solid. Thiswas purified by column chromatography on silica gel (eluent : ethylacetate/heptane 1:9 to 1:4) to give 1,2-dimethoxy-4,5-bis(chloromethyl)benzene (19.98 g) as a white solid, which was used without furtherpurification.

EXAMPLE 38

[0572] Diethyl 4-(2-propyl)oxyindan-2,2-dicarboxylate, 38a.

[0573] (Intermediate)

[0574] Sodium hydride (7.7 g, 50-60% dispersion in oil) was renderedoil-free by washing with heptane (twice). This was then added to asolution of 2,3-di(bromomethyl)-1-(2-propyl)oxybenzene (21 g) in THF(600 ml) and the solution was heated to reflux. A solution of diethylmalonate (10.4 g) in THF (150 ml) was added drop-wise over 1 hour. Aftera further hour, the solution was cooled to room temperature, and water(200 ml) was added drop-wise to decompose the excess sodium hydride. Themixture was poured into aqueous hydrochloric acid (500 ml, 3 M) and wasextracted with ethyl acetate (3×300 ml). The general workup proceduregave a dark oil which was purified by column chromatography on silicagel (eluent:ethyl acetate/heptane 1:9) to give diethyl4-(2-propyl)oxyindan-2,2-dicarboxylate (11.5 g) as a clear oil, whichwas used without further purification.

EXAMPLE 39

[0575] 4-(2-Propyl)oxyindan-2,2-dicarboxylic acid, 39a.

[0576] (Intermediate)

[0577] A solution/suspension of diethyl4-(2-propyl)oxyindan-2,2-dicarboxylate (11.5 g) in potassium hydroxidesolution (50 ml, 3 M) was heated at reflux for 18 hours. The solutionwas cooled to room temperature and was extracted with ether. The aqueouswas acidified to pH<1 with aqueous hydrochloric acid (3 M) and wasextracted with ethyl acetate. The standard workup afforded4-(2-propyl)oxyindan-2,2-dicarboxylic acid (8.5 g) as a brown solid,which was used without further purification.

EXAMPLE 40

[0578] 4-(2-Propyl)oxyindan-2-carboxylic acid, 40a.

[0579] (Intermediate)

[0580] A solution of 4-(2-propyl)oxyindan-2,2-dicarboxylic acid (11.5 g)in NMP (20 ml) was heated to 150° C. After a further 15 minutes, thesolution was allowed to cool to room temperature, and was poured intoaqueous hydrochloric acid (1500 ml, 1 M). This mixture was extractedwith ethyl acetate (2×500 ml) and a standard workup gave4-(2-propyl)oxyindan-2-carboxylic acid (3.98 g) as a dark brown solid,which was used without further purification.

[0581] With compound 37b as starting material following the proceduresin Examples 38, 39 and 40, the following compound was prepared:

[0582] 5,6-Dimethoxyindan-2-carboxylic acid, 40b

EXAMPLE 41

[0583]6-Chloro-3-[1-[3-(2,3-dihydro-1H-indol-1-yl)-3-oxopropan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole41a.

[0584] To a solution of indoline (6.0 g) and triethylamine (15.8 g) inTHF (200 ml) was added a mixture of 3-chloropropionyl chloride (6.6 g)and THF (100 ml) at 5-9° C. The mixture was allowed to warm to roomtemperature, evaporated to dryness in vacuo and subjected topurification on silica gel eluted with ethyl acetate-heptane (1:2) togive a crystalline compound (5.6 g). The compound was dissolved inbutanone (200 ml) and added to a boiling mixture of6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (5.8 g),triethylamine (18.6 ml), and butanone (400 ml). The resulting mixturewas boiled under reflux for 3 h, evaporated in vacuo, and the residuewas purified on silica gel eluted with THF-triethylamine (95:5) to givea crystalline compound (5.4 g). The title compound was obtained aftercrystallization (THF-ethyl acetate-heptane).

[0585]¹H NMR (DMSO-d₆) δ2.50 (broad s, 3H), 2.65-2.85 (m, 5H), 3.05-3.20(m, 4H), 4.15 (t, 2H), 6.10 (broad s, 1H), 6.95 (t, 1H). 7.05 (d, 1H),7.15 (t, 1H), 7.25 (d, 1H), 7.40 (broad s, 2H), 7.80 (d, 1H), 8.10 (d,1H), 11.20 (broad s, 1H).

[0586] The following compound was made in a similar manner:

[0587]6-Chloro-3-[1-[4-(2,3-dihydro-1H-indol-1-yl)-4-oxobutan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole41 b.

[0588]¹H NMR (DMSO-d₆) δ1.85 (t, 2H), 2.40-2.55 (m, 6H), 2.65 (t, 2H),3.10 (broad s, 4H), 4.10 (t, 2H), 6.10 (broad s, 1H), 6.95 (t, 1H), 7.05(d, 1H), 7.15 (t, 1H), 7.20 (d, 1H), 7.35-7.45 (m, 2H), 7.80 (d, 1H),8.10 (d, I H), 11.20 (broad s, 1H).

EXAMPLE 42

[0589]6-Chloro-3-[1-[3-(2,3-dihydro-1H-indol-1-yl)propan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole42a.

[0590] The compound was prepared from 41a as described in Example 11 butby the use of alane instead of LiAlH4 for the reduction.

[0591]¹H NMR (DMSO-d₆) δ 1.75 (q, 2H), 2.40-2.60 (m, 4H), 2.65 (t, 2H),2.90 (t, 2H), 3.00-3.20 (m, 4H), 3.25-3.40 (m. 2H), 6.10 (broad s, 1H),6.40-6.60 (m, 2H), 6.90-7.10 (m, 3H), 7.40-7.50 (m, 2H), 7.80 (d, 1H),11.20 (broad s, 1H).

[0592] Pharmacological Testing

[0593] The compounds of the invention were tested in well recognised andreliable methods. The tests were as follows:

[0594]³H-YM-69151-2 BINDING

[0595] By this method the inhibition by drugs of the binding of thedopamine D₄ antagonist ³H-YM-09151-2 to dopamine D₄ receptors in clonedhuman dopamine receptor subtype 4.2 membranes is determined in vitro.Accordingly, this is a test for affinity for dopamine D₄ receptors. Thetest is performed using a preparation of cloned dopamine D₄ cellmembranes CRM-016®, Dupharma A/S, Denmark, in accordance with theproduct specifications. The results are given in the following Table 1as IC₅₀-values. TABLE 1 Binding Data (IC₅₀ values in nM or % inhibitionof binding at 50 nM) Comp. Comp. Comp. Comp No. D₄-bind. No. D₄-bind.No. D₄-bind. No. D₄-bind. 5a 3.5 11b 3.0 20d 3.0 25a 27 5b 5.0 11c 3.820e 21% 25b 5.3 5c 32.0 11 27.0 20f 3.2 28a 160.* 5d 20.0 11e 16.0 20g16.0 28b 14.0 6a 6.8 11f 1.6 20h 30.0 28c 13.0 6b 3.3 11g 12.0 20i 2.9*29a 6.9 6c 12.0 11h 24.0 20j 6.9 29b 2.2 6e 84.0 11i 37% 20k 10.0 30a9.9 6d 30.0 11j nt. 20l nt. 30b nt. 8a 3.5 16a 6.2 20m 8.4 31a nt. 8b2.8 18a 7.3 21a 0.48 34a 4.0 8c 2.3 18b 4.3 21b 2.1 34b 24.0 8d 20.0*18c 41.0 21c 1.8 35 nt. 8e 8.3 18d 7.3 21d 3.9 8f 12.0 18e 66.0 21e 23.08g 14.0 20a 3.1 21f 3.2 8h 34.0 20b 6.7 21g 7.2 11a 2.8 20c 2.4 21h 14.0

[0596]³H-8-OH-DPAT Binding.

[0597] By this method the inhibition by drugs of the binding of the5-HT_(1A) agonist ³H-8-OH-DPAT (1 nM) to 5-HT_(1A) receptors inmembranes from rat brain minus cerebellum is determined in vitro.Accordingly, this is a test for affinity for 5-HT_(1A) receptor. Thetest is performed as described by Hyttel et al., Drug. Dev. Res., 1988,15, 389-404.

[0598]³H-Ketanserin Binding.

[0599] By this method the inhibition by drugs of the binding of³H-Ketanserin (0.5 nM) to 5-HT_(2A) receptors in membranes from rat isdetermined in vitro The method is described in Hyttel, Pharmacology &Toxicology, 61, 126-129, 1987

[0600] In addition to the above tests, the compounds of the inventionwere tested with respect to affinity for the dopamine D₂ receptor bydetermining their ability to inhibit the binding of ³H-spiroperidol toD₂ receptors by the method of Hyttel et al, J. Neurochem., 1985, 44,1615. Furthermore, the compounds were tested with respect to their 5-HTreuptake inhibiting effect by measuring their ability to inhibit theuptake of ³H-serotonin into whole rat brain synaptosomes in vitro. Theassay was performed as described by Hyttel, J. , Psychopharmacology,1978, 60, 13.

[0601] In general, the compounds of the invention have been foundpotently to inhibit the binding of tritiated YM-09151-2 to dopamine D₄receptors. In addition many compounds have proven to be potent 5-HTreuptake inhibitors and many of the compounds have been found to inhibitthe binding of tritiated 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT)to 5-HT_(1A) receptors and/or the binding of ³H ketanserin to 5-HT_(2A)receptors in vitro. Some compounds only bind to one of the two serotoninreceptor subtypes, 5-HT_(1A) or 5-HT_(2A). The compounds have nosubstantial or only weak affinity for the dopamine D₂ receptor.

[0602] The VTA model is used to examine the effects on spontaneousactive DA neurones in the ventral tegmental area (VTA) upon repeatedoral treatment. Inhibition of the number of active DA neurones in VTAindicates an antipsychotic effect of a compound. The VTA model isdescribed more fully in EP-A2-392 959 on page 4.

[0603] Some of the compounds of the invention has been tested and foundeffective in reducing the number of active DA neurons in the VTA.

[0604] Accordingly, the compounds of the invention are considered usefulin the treatment of positive and negative symptoms of schizophrenia,other psychoses, anxiety disorders, such as generalised anxietydisorder, panic disorder, and obsessive compulsive disorder, depression,alcohol abuse, impulse control disorders aggression, side effectsinduced by conventional antipsychotic agents, ischaemic disease states,migraine, senile dementia and cardiovascular disorders and in theimprovement of sleep. In particular the compounds of the invention areconsidered useful in the treatment of positive and negative symptoms ofschizophrenia without inducing extrapyramidal side effects.

[0605] Formulation Examples

[0606] The pharmaceutical formulations of the invention may be preparedby conventional methods in the art.

[0607] For example: Tablets may be prepared by mixing the activeingredient with ordinary adjuvants and/or diluents and subsequentlycompressing the mixture in a conventional tabletting machine. Examplesof adjuvants or diluents comprise: corn starch, potato starch, talcum,magnesium stearate, gelatine, lactose, gums, and the like. Any otheradjuvants or additives usually used for such purposes such ascolourings, flavourings, preservatives etc. may be used provided thatthey are compatible with the active ingredients.

[0608] Solutions for injections may be prepared by dissolving the activeingredient and possible additives in a part of the solvent forinjection, preferably sterile water, adjusting the solution to desiredvolume, sterilisation of the solution and filling in suitable ampules orvials. Any suitable additive conventionally used in the art may beadded, such as tonicity agents, preservatives, antioxidants, etc.Typical examples of recipes for the formulation of the invention are asfollows: 1) Tablets containing 5.0 mg of Compound 4a calculated as thefree base: Compound 5a 5.0 mg Lactose 60 mg Maize starch 30 mgHydroxypropylcellulose 2.4 mg Microcrystalline cellulose 19.2 mgCroscarmellose Sodium Type A 2.4 mg Magnesium stearate 0.84 mg 2)Tablets containing 0.5 mg of Compound 21 calculated as the free base:Compound 21 0.5 mg Lactose 46.9 mg Maize starch 23.5 mg Povidone 1.8 mgMicrocrystalline cellulose 14.4 mg Croscarmellose Sodium Type A 1.8 mgMagnesium stearate 0.63 mg 3) Syrup containing per milliliter: Compound21 25 mg Sorbitol 500 mg Hydroxypropylcellulose 15 mg Glycerol 50 mgMethyl-paraben 1 mg Propyl-paraben 0.1 mg Ethanol 0.005 ml Flavour 0.05mg Saccharin natrium 0.5 mg Water ad 1 ml 4) Solution for injectioncontaining per milliliter: Compound 4a 0.5 mg Sorbitol 5.1 mg AceticAcid 0.05 mg Saccharin sodium 0.5 mg Water ad 1 ml

What is claimed is:
 1. A substituted indane or dihydroindole compound ofFormula I

wherein A is a group

Y is a hydrocarbon group completing an indane ring, a group NR¹completing a dihydroindole ring, or a group N completing a dihydroindolering linked via the 1-position; W is a bond, and n+m is 1, 2, 3, 4, 5,or 6; W is CO, SO, or SO₂, n is 2, 3, 4, or 5 and m is 0, 1, 2, or 3,provided that n+m is not more than 6; or W is O, S, n is 2, 3, 4, or 5,and m is 0, 1, 2, or 3, provided that n+m is not more than 6, andprovided that if Y is N completing a dihydroindole ring attached via the1-position then m is 2, or 3; and if Y is NR¹ completing a dihydroindolering linked via the 2-position then m is 1, 2, or 3; R¹ is hydrogen,C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, aryl, heteroaryl,aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆alkyl, acyl, thioacyl,C₁₋₆alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl, orheteroarylsulfonyl; R¹⁵VCO— wherein V is O or S and R¹⁵ isC₁₋₆-alk(en/yn)yl, C₃₋₈cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, aryl, or heteroaryl; or a groupR¹⁶R¹⁷NCO— or R¹⁶R¹⁷NCS— wherein R¹⁶ and R¹⁷ are independently hydrogen,C₁₋₆alk(en)/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, heteroaryl, or aryl, or R¹⁶ andR¹⁷ together with the N-atom to which they are linked, form apyrrolidinyl, piperidinyl or perhydroazepin group; and R²-R⁵ areindependently selected from hydrogen, halogen, cyano, nitro,C₁₋₆-alk(en/yn)yl, C₁₋₆ alkoxy, C₁₋₆-alkylthio, hydroxy,C₃₋₈-cycloalk(en)yl, C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,C₁₋₆-alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl,trifluoromethyl, trifluoromethylsulfonyloxy and C₁₋₆alkylsulfonyl, oneof R²-R⁵ alternatively being a group —NR¹³R ¹⁴ wherein R¹³ is as definedfor R¹ and R¹⁴ is hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆alk(en/yn)yl, aryl, heteroaryl, aryl-C₁₋₆ alkyl,or heteroaryl-C₁₋₆-alkyl, or R¹³ and R¹⁴ together with the N-atom towhich they are linked form a group

wherein Q is C═O, C═S or CH₂; T is NH, N-alkyl, S, O or CH₂; and p is1-4, inclusive; or two adjacent groups taken from R²-R⁵ may be joinedand designate a —(CH₂)₃—, or —CH═CH—NH—, thereby forming a fused 5membered ring; R⁶-R⁹ and R1 ¹¹-R¹² are independently hydrogen, halogen,cyano, nitro, C₁₋₆-alk(en/yn)yl, C ₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,C₃₋₈-cycloalk(en)yl, C₃₋₈-cycloalk(en)yl-C₁₋₆alk(en/yn)yl, aryl,heteroaryl, phenylcarbonyl, halogen substituted phenylcarbonyl,trifluoromethyl, or C₁₋₆ alkylsulfonyl, or two adjacent groups takenfrom R⁶-R⁹ may together form a methylenedioxy group; R¹⁰ is as definedfor R¹ above, with the proviso that the substituent R³ or R⁴ in position6 may not be —NR¹³R¹⁴ when Y is CH₂, W is a bond, n+m is 1 and the ringis linked via the 1-position; or a pharmaceutically acceptable acidaddition salt thereof.
 2. A compound of claim 1 , wherein Y is CH₂.
 3. Acompound of claim 1 , wherein Y is NR¹ or N completing a dihydroindolering.
 4. A compound of claim 3 , wherein Y is NR¹ and that the resultingdihydroindole ring is linked to the (CH₂)_(n)—W—(CH₂)_(m) group via the2- or 3-position.
 5. A compound of claim 3 , wherein Y is N and theresulting dihydroindole is linked to the (CH₂)_(n)—W—(CH₂)m group viathe 1-position.
 6. A compound of claim 2 , wherein A is a group a)linked to X via the 2 or the 3 position, or a group b).
 7. A compound ofclaim 6 , wherein A is a group a) linked to X via the 2 or the 3position.
 8. A compound of claim, 2, wherein A is a group c) linked to Xvia the 4, 5, 6, or 7 position.
 9. A compound of claim 3 , wherein A isa group a) linked to X via the 2 or the 3 position, or a group b).
 10. Acompound of claim 9 , wherein A is a group a) linked to X via the 2 orthe 3 position.
 11. A compound of claim 3 , wherein A is a group c)linked to X via the 4, 5, 6, or 7 position.
 12. A compound of claim 1 ,wherein Y is NR¹ or N completing a dihydroindole ring and A is a groupa) linked to X via the 2 or the 3 position.
 13. A compound of claim 2 ,wherein the indane is linked via the 2 position and A is a group a)which is linked via position
 3. 14. A compound of claim 2 , wherein theindane is linked via the 2 position and A is a group a) which is linkedvia position
 2. 15. A compound of claim 2 , wherein the indane is linkedvia the 2 position and A is a group b).
 16. A compound of claim 2 ,wherein the indane is linked via the 2 position and A is a group c)which is linked via position 4, 5, 6, or
 7. 17. A compound of claim 2 ,wherein the indane is linked via the 1 position and A is a group a)which is linked via position
 3. 18. A compound of claim 2 , wherein theindane is linked via the 1 position and A is a group a) which is linkedvia position
 2. 19. A compound of claim 2 , wherein the indane is linkedvia the 1 position and A is a group b).
 20. A compound of claim 2 ,wherein the indane is linked via the 1 position and A is a group c)which is linked via position 4, 5, 6, or
 7. 21. A compound of claim 4 ,wherein the dihydroindole ring is linked via the 3 position and A is agroup a) which is linked via position
 3. 22. A compound of claim 4 ,wherein the dihydroindole ring is linked via the 3 position and A is agroup a) which is linked via position
 2. 23. A compound of claim 4 ,wherein the dihydroindole ring is linked via the 3 position and A is agroup b).
 24. A compound of claim 4 , wherein the dihydroindole ring islinked via the 3 position and A is a group c) which is linked viaposition, 4, 3, 6, or
 7. 25. A compound of claim 4 , wherein thedihydroindole ring is linked via the 2 position and A is a group c)which is linked via position
 3. 26. A compound of claim 4 , wherein thedihydroindole ring is linked via the 2 position and A is a group a)which is linked via position
 2. 27. A compound of claim 4 , wherein thedihydroindole ring is linked via the 2 position and A is a group b). 28.A compound of claim 4 , wherein the dihydroindole ring is linked via the2 position and A is a group c) which is linked via position 4, 5, 6, or7.
 29. A compound of claim 5 , wherein A is a group a) which is linkedvia position
 3. 30. A compound of claim 5 , wherein A is a group a)which is linked via position
 2. 31. A compound of claim 5 , wherein A isa group b).
 32. A compound of claim 5 , wherein A is a group c) which islinked via position 4, 5, 6, or
 7. 33. A compound of claim 1 , wherein Wis a bond and m+n is 1 to
 4. 34. A compound of claim 1 , wherein W is abond and m+n is 1 to
 2. 35. A compound of claim 1 , wherein W is a bondand m+n is
 1. 36. A compound of claim 1 , wherein W is a bond and m+n is2.
 37. A compound of claim 1 , wherein W is a bond and m+n is 2 to 6.38. A compound of claim 1 , wherein W is a bond and m+n is 2 to
 5. 39. Acompound of claim 1 , wherein W is a bond and m+n is 2 to
 4. 40. Acompound of claim 1 , wherein W is a bond and m+n is 3 to
 6. 41. Acompound of claim 1 , wherein W is a bond and m+n is 3 to
 5. 42. Acompound of claim 1 , wherein W is a bond and m+n is 3 to
 4. 43. Acompound according to claim 1 , wherein W is O.
 44. A compound accordingto claim 1 , wherein W is CO.
 45. A compound of claim 1 , wherein R¹ ishydrogen, C₁₋₆-alkyl, formyl, C₁₋₆-alkylcarbonyl, C₁₋₆-alkoxycarbonyl orC₁₋₆-alkylaminocarbonyl and R² to R⁵ are independently selected fromhydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₁₋₆alkoxy, C₁₋₆-alkylthio,hydroxy, C₃₋₈cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkylcarbonyl,trifluoromethyl, trifluoromethylsulfonyloxy and C₁₋₆alkylsulfonyl, oneof R² to R⁵ alternatively being a group —NR¹³R¹⁴ wherein R¹³ ishydrogen, C₁₋₆-alkyl, acyl, C₁₋₂-alkylsulfonyl, or a group —R¹⁶R¹⁷NCOwherein R¹⁶ is hydrogen, C₁₋₆-alkyl, C₃₋₈-cycloalkyl, orC₃₋₈-cycloalkyl-C₁₋₆alkyl, and R¹⁷ is hydrogen or C₁₋₆-alkyl, or R¹⁶ andR¹⁷ together with the N-atom to which they are linked, form apyrrolidinyl, piperidinyl, or perhydroazepin group and R¹⁴ is hydrogenor C₁₋₆-alkyl, or R¹³ and R¹⁴ are linked together to form pyrrolidinyl,piperidinyl, perhydroazepin or a 5 to 7 membered unsubstituted lactamring.
 46. A compound of claim 45 , wherein R² to R⁵ is selected fromhydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₁₋₆-alkoxy,trifluoromethyl, and trifluoromethylsulfonyloxy.
 47. A compound of claim1 , wherein none of R²-R⁵ is a group NR¹³R¹⁴.
 48. A compound of claim 1, wherein at least one of R²-R⁵ is a group NR¹³R¹⁴.
 49. A compound ofclaim 48 wherein R¹³ is methyl, formyl, acetyl, methylaminocarbonyl,dimethylaminocarbonyl, methylsulfonyl, aminocarbonyl,cyclopropylcarbonyl, pyrrolidinylcarbonyl or 4-fluorophenylaminocarbonyland R¹⁴ is hydrogen or C₁₋₆-alkyl.
 50. A compound of claim 1 , whereintwo adjacent groups taken from R² to R⁵ are joined and designate—CH═CH—NH—, thereby forming a fused 5 membered ring.
 51. A compound ofclaim 45 , wherein R⁶ to R⁹ are independently hydrogen, halogen, cyano,nitro, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, trifluoromethyl, orC₁₋₆alkylsulfonyl, or two adjacent groups taken from R⁶-R⁹ may be joinedand designate a methylenedioxy group; R¹¹ and R¹² are hydrogen orC₁₋₆-alkyl, and R¹⁰ is hydrogen, C₁₋₆-alkyl, or acyl.
 52. A compound ofclaim 51 wherein R⁶ to R⁹ are independently selected from hydrogen,halogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, or two adjacent groups taken fromR⁶-R⁹ may be joined and designate a methylenedioxy group.
 53. A compoundof claim 52 wherein R⁹ is hydrogen.
 54. A compound of claim 53 whereinR⁸ is hydrogen.
 55. A compound of claim 54 wherein R⁶ to R⁷ areindependently hydrogen or halogen.
 56. A compound of claim 55 wherein R⁶to R⁷ are independently hydrogen or chloro.
 57. A pharmaceuticalcomposition comprising a compound of claim 1 in a therapeuticallyeffective amount together with one or more pharmaceutically acceptablecarriers or diluents.
 58. A method of treating the positive and negativesymptoms of schizophrenia, other psychoses, anxiety disorders,depression, alcohol abuse, impulse control disorders, aggression,ischaemic disease states, migraine, senile dementia and cardiovasculardisorders and in the improvement of sleep comprising administration of atherapeutically acceptable amount of a compound according to claim 1 .59. The method of claim 58 , wherein said anxiety disorders are selectedfrom the group consisting of generalized anxiety disorder, panicdisorder and obsessive compulsive disorder.